KR102464270B1 - Heterobifunctional monodisperse polyethylene glycol and complex using same - Google Patents
Heterobifunctional monodisperse polyethylene glycol and complex using same Download PDFInfo
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- KR102464270B1 KR102464270B1 KR1020197028712A KR20197028712A KR102464270B1 KR 102464270 B1 KR102464270 B1 KR 102464270B1 KR 1020197028712 A KR1020197028712 A KR 1020197028712A KR 20197028712 A KR20197028712 A KR 20197028712A KR 102464270 B1 KR102464270 B1 KR 102464270B1
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- polyethylene glycol
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- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 90
- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 86
- 125000000524 functional group Chemical group 0.000 claims abstract description 102
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- 229940079593 drug Drugs 0.000 claims description 62
- 239000003814 drug Substances 0.000 claims description 62
- -1 1H-1,2,3-triazole-1,4-diyl structure Chemical group 0.000 claims description 46
- 150000002430 hydrocarbons Chemical group 0.000 claims description 26
- 229940125644 antibody drug Drugs 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims 1
- 125000003827 glycol group Chemical group 0.000 abstract description 10
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 230000000052 comparative effect Effects 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 25
- 238000005259 measurement Methods 0.000 description 24
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
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- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical group C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 6
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- 239000011780 sodium chloride Substances 0.000 description 6
- WOJKKJKETHYEAC-UHFFFAOYSA-N 6-Maleimidocaproic acid Chemical compound OC(=O)CCCCCN1C(=O)C=CC1=O WOJKKJKETHYEAC-UHFFFAOYSA-N 0.000 description 5
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- 230000002194 synthesizing effect Effects 0.000 description 5
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 4
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Abstract
근접한 2개의 단분산 폴리에틸렌 글리콜 측쇄를 가지며, 분자 구조 중에 키랄 중심을 가지지 않는 헤테로이관능성 단분산 폴리에틸렌 글리콜을 제공한다. 하기 식 (1)로 표시되는, 헤테로이관능성 단분산 폴리에틸렌 글리콜.
여기서, X1 및 Y1은 각각 생체기능성 분자에 존재하는 관능기와 반응하여 공유결합을 형성하는 관능기를 적어도 포함하는 원자단이다. R1은 탄화수소기 등이다. n은 3 내지 72의 정수이다. A1은 -L1-(CH2)m1- 등을 나타내고, L1 및 L2은 에테르 결합 등을 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수를 나타낸다. B1은 -L3-(CH2)m3- 등을 나타내고, L3 및 L4은 아미드 결합 등을 나타내고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수를 나타낸다.A heterobifunctional monodisperse polyethylene glycol having two monodisperse polyethylene glycol side chains in close proximity and having no chiral center in the molecular structure is provided. A heterobifunctional monodisperse polyethylene glycol represented by the following formula (1).
Here, each of X 1 and Y 1 is an atomic group including at least a functional group that reacts with a functional group present in the biofunctional molecule to form a covalent bond. R 1 is a hydrocarbon group or the like. n is an integer from 3 to 72; A 1 represents -L 1 -(CH 2 ) m1 - and the like, L 1 and L 2 represent an ether bond, etc., and m1 and m2 each independently represent an integer of 1 to 5. B 1 represents -L 3 -(CH 2 ) m3 - and the like, L 3 and L 4 represent an amide bond, etc., and m3 and m4 each independently represent an integer of 1 to 5.
Description
본 발명은 2개의 상이한 화학적 반응성 관능기들을 갖는 헤테로이관능성 단분산 폴리에틸렌 글리콜에 관한 것이다. 보다 구체적으로, 생리 활성 단백질, 펩티드, 항체, 핵산 또는 저분자량 약물 등의 생체기능성 분자, 약물 전달 시스템 중의 약물 캐리어, 진단용 재료, 의료용 디바이스 등의 수식 (modification)에 이용되며, 이것은 특히 항체 의약의 수식에 유용한 헤테로이관능성 단분산 폴리에틸렌 글리콜 및 그것을 이용한 복합체에 관한 것이다.The present invention relates to heterobifunctional monodisperse polyethylene glycols having two different chemically reactive functional groups. More specifically, it is used for modification of biofunctional molecules such as bioactive proteins, peptides, antibodies, nucleic acids or low molecular weight drugs, drug carriers in drug delivery systems, diagnostic materials, medical devices, etc. It relates to a heterobifunctional monodisperse polyethylene glycol useful for modification and a complex using the same.
항체-약물 복합체 (Antibody-Drug Conjugate: ADC)는, 항체에 약물을 결합시켜, 항체의 항원 특이성을 이용하여 약제를 질환 부위에 능동적으로 운반하는 것을 목적으로 하는 항체 의약이며, 최근에, 암 치료의 분야에서 가장 급속히 성장하고 있는 기술 중 하나이다. ADC는 항체, 약물, 및 항체와 약물 사이를 결합시키는 링커의 각 부분으로 구성된다.Antibody-Drug Conjugate (ADC) is an antibody drug for the purpose of actively delivering a drug to a disease site by binding a drug to an antibody and using the antigen specificity of the antibody, and recently, cancer treatment It is one of the fastest growing technologies in the field of ADCs consist of each part of an antibody, a drug, and a linker that connects the antibody and drug.
ADC에 이용되는 다수의 약물은 소수성이며, 이들 소수성 약물을 항체에 복수 결합하여 ADC를 제조하는 경우, 약물의 소수성에 기인하는 응집의 발생이나 항체의 혈중 안정성의 저하가 문제가 된다. 따라서, 항체 당 탑재 가능한 약물의 수에 제약이 생기고, 결과적으로 ADC의 약효를 충분히 얻을 수 없는 경우가 있다.Many drugs used in ADC are hydrophobic, and when an ADC is prepared by combining a plurality of these hydrophobic drugs to an antibody, the occurrence of aggregation due to the hydrophobicity of the drug or a decrease in the blood stability of the antibody becomes a problem. Therefore, there is a restriction on the number of drugs that can be loaded per antibody, and as a result, there are cases in which the drug efficacy of the ADC cannot be sufficiently obtained.
이 과제에 대하여 검토되고 있는 해결 방법 중 하나가, 친수성 링커의 이용이다. 친수성 링커로서 폴리에틸렌 글리콜, 친수성 펩티드, 당쇄 등이 이용되고 있다. 특히, 폴리에틸렌 글리콜은 항원성이 낮고, 생체 적합성이 높기 때문에, 현재, 임상시험 또는 전-임상시험 단계에 있는 복수의 ADC에 채용되고 있다.One of the solutions being investigated with respect to this subject is the use of a hydrophilic linker. Polyethylene glycol, hydrophilic peptides, sugar chains and the like are used as hydrophilic linkers. In particular, since polyethylene glycol has low antigenicity and high biocompatibility, it is currently employed in a plurality of ADCs in clinical trials or pre-clinical trials.
ADC 분야에서는, ADC의 균일성을 보증하고, 정제, 분석 및 의약품 승인 신청을 간편하게 하는 것을 목적으로 하고, 특정의 에틸렌글리콜 쇄장을 가지는 성분이90% 이상 포함되는 화합물이 사용된다. 이러한 화합물은, 단분산 폴리에틸렌 글리콜이라고 칭해진다.In the ADC field, a compound containing 90% or more of a component having a specific ethylene glycol chain length is used for the purpose of ensuring the uniformity of the ADC and simplifying purification, analysis, and drug approval application. Such a compound is called monodisperse polyethylene glycol.
단분산 폴리에틸렌 글리콜을 ADC에 대한 링커로서 이용하는 경우, 항체와 약물을 구별하여 결합시킬 필요가 있기 때문에, 2개의 상이한 화학적 반응성 관능기들을 갖는 헤테로이관능성 단분산 폴리에틸렌 글리콜이 이용된다. 일반적으로, 단분산 폴리에틸렌 글리콜 쇄의 양 말단에 서로 상이한 화학적 반응성 관능기를 가지는 화합물을 이용하여 ADC가 제조된다.When monodisperse polyethylene glycol is used as a linker for ADC, heterobifunctional monodisperse polyethylene glycol having two different chemically reactive functional groups is used because it is necessary to bind the antibody to the drug separately. In general, ADCs are prepared using compounds having different chemically reactive functional groups at both ends of monodisperse polyethylene glycol chains.
그런데, 최근, 단분산 폴리에틸렌 글리콜을 항체와 약물을 연결하는 링커 주쇄로서 이용하는 것이 아니라, 항체와 약물을 연결하는 분기 링커에 측쇄로서 단분산 폴리에틸렌 글리콜을 도입한 ADC가 보고되고 있다.However, recently, instead of using monodisperse polyethylene glycol as a main chain of a linker connecting an antibody and a drug, ADCs in which monodisperse polyethylene glycol is introduced as a side chain to a branched linker connecting an antibody and a drug have been reported.
비특허문헌 1에서는, 항체와 약물을 연결하는 링커 주쇄로서 단분산 폴리에틸렌 글리콜을 이용한 ADC, 및 항체와 약물을 연결하는 분기 링커의 측쇄로서 단분산 폴리에틸렌 글리콜을 이용한 ADC의 약물 동태 및 이들의 치료 효과를 비교하고 있으며, 후자의 ADC가 약물의 소수성을 차폐하는(masking) 효과가 높고, 뛰어난 약물 동태 및 치료 효과를 나타내는 것이 보고되고 있다.In
또한, 특허문헌 2 및 특허문헌 3에서는, 분기 링커의 측쇄로서 단분산 폴리에틸렌 글리콜을 가지는 다양한 타입의 ADC, 및 이들 ADC를 제조하기 위한 중간체가 개시되고 있다.In addition, Patent Document 2 and Patent Document 3 disclose various types of ADCs having monodisperse polyethylene glycol as a side chain of a branched linker, and intermediates for producing these ADCs.
또한, 특허문헌 1에는, 펜타에리트리톨 골격으로 2개의 폴리에틸렌 글리콜쇄와 2개의 관능기와 결합되는 폴리에틸렌 글리콜 유도체가 기재되어 있다.In addition,
발명의 요약Summary of the invention
발명이 해결하려는 과제The problem the invention is trying to solve
특허 문헌 1에는, 펜타에리트리톨 골격에 2개의 동일한 관능기와 2개의 동일한 폴리에틸렌 글리콜쇄가 결합된 화합물만이 개시되어 있다. 이것은, 관능기화의 반응에서, 펜타에리트리톨의 2개의 수산기를 보호기로 보호하고, EO의 첨가 후, 보호기가 제거된 후, 관능기화가 수행되기 때문이다.
비특허 문헌 1, 특허 문헌 2 또는 특허 문헌 3에 기재되어 있는, 분기 링커의 측쇄로서 단분산 폴리에틸렌 글리콜을 가지는 ADC는, 단분산 폴리에틸렌 글리콜이 결합한 링커의 분기 부분에 비대칭 탄소(asymmetric carbon)를 가지는 아미노산이 이용되고 있다.ADCs having monodisperse polyethylene glycol as a side chain of a branched linker described in
이러한 키랄 중심을 갖는 화합물을 이용하여, 다양한 화학적 변환 공정을 통해 원하는 화학 구조의 링커를 구축하는 경우, 화학적 변환 공정에 포함되는, 예를 들면 산성 또는 알칼리성의 반응 조건, 유기 촉매 또는 무기 촉매 존재 하에서의 반응, 또는 축합제의 존재 하에서의 반응 등에 있어서, 키랄 중심에 원하지 않는 부분적인 입체적 반전(steric inversion)이나 라세미화가 일어나므로, 입체이성체의 혼합물이 형성될 가능성이 있다. 입체이성체의 혼합물로부터 원하는 3차원 구조를 갖는 화합물을 단리하는 것은 극히 어렵다. 이러한 입체이성체의 혼합물을 링커로서 항체와 약물을 결합시켰을 경우, 불균질인 ADC가 형성되므로 바람직하지 않다.When a linker of a desired chemical structure is constructed through various chemical conversion processes using a compound having such a chiral center, for example, acidic or alkaline reaction conditions, organic catalysts or inorganic catalysts in the chemical conversion process. In the reaction or reaction in the presence of a condensing agent, undesired partial steric inversion or racemization occurs at the chiral center, so that a mixture of stereoisomers may be formed. It is extremely difficult to isolate a compound having a desired three-dimensional structure from a mixture of stereoisomers. When the mixture of these stereoisomers is combined with an antibody and a drug as a linker, it is not preferable because heterogeneous ADC is formed.
또한, 특허 문헌 2 또는 특허 문헌 3에서는, 분기 링커의 측쇄에 2개 이상의 단분산 폴리에틸렌 글리콜을 갖는 ADC도 또한 개시되고 있다. 그러나, 각각의 단분산 폴리에틸렌 글리콜 측쇄의 결합 위치가 떨어져 있어 복수개의 폴리에틸렌 글리콜쇄를 가지는 분기형 폴리에틸렌 글리콜의 특징인, 우산형(umbrella-like) 구조(Biomaterials 2001, 22(5), 405-417)에 의한 소수성 약물에 대한 차폐 효과가 작고, 복수의 단분산 폴리에틸렌 글리콜 측쇄의 존재로 인한 이점을 유효하게 활용할 수 없다.Further, in Patent Document 2 or Patent Document 3, ADC having two or more monodisperse polyethylene glycols in the side chain of a branched linker is also disclosed. However, since the bonding positions of each monodisperse polyethylene glycol side chain are separated, an umbrella-like structure (Biomaterials 2001, 22(5), 405-417, which is a characteristic of branched polyethylene glycol having a plurality of polyethylene glycol chains) ), the shielding effect for hydrophobic drugs is small, and the advantage due to the presence of a plurality of monodisperse polyethylene glycol side chains cannot be effectively utilized.
본 발명의 과제는, 근접한 2개의 단분산 폴리에틸렌 글리콜 측쇄를 가지며, 분자 구조 중에 키랄 중심을 가지지 않는 헤테로이관능성 단분산 폴리에틸렌 글리콜, 및 이것을 이용하여 항체와 약물을 결합한 항체-약물 복합체를 제공하는 것이다.An object of the present invention is to provide a heterobifunctional monodisperse polyethylene glycol that has two adjacent monodisperse polyethylene glycol side chains and does not have a chiral center in the molecular structure, and an antibody-drug complex that binds an antibody and a drug using the same. .
본 발명자들은, 상기의 과제를 해결할 수 있도록 열심히 연구를 거듭한 결과, 2개의 단분산 폴리에틸렌 글리콜 측쇄가 서로 근접하게 결합하여, 분자 구조 중에 키랄 중심을 갖지 않는 헤테로이관능성 단분산 폴리에틸렌 글리콜, 및 이것을 이용하여 항체와 약물을 결합한 항체-약물 복합체를 개발하였다.The present inventors, as a result of repeated studies to solve the above problems, have a heterobifunctional monodisperse polyethylene glycol having two monodisperse polyethylene glycol side chains closely bonded to each other and having no chiral center in the molecular structure, and this An antibody-drug complex that combines an antibody and a drug was developed using
또한, 본 발명의 헤테로이관능성 단분산 폴리에틸렌 글리콜은, 2개의 단분산 폴리에틸렌 글리콜 측쇄가 분기 부분의 4급 탄소 원자에 안정적인 에테르 결합으로 결합하고 있기 때문에, 당해 헤테로이관능성 단분산 폴리에틸렌 글리콜의 구조의 화학 변환 공정에 있어서, 단일-사슬의 단분산 폴리에틸렌 글리콜로 분해하기 어려운 특징을 가진다.In addition, in the heterobifunctional monodisperse polyethylene glycol of the present invention, since two monodisperse polyethylene glycol side chains are bonded to the quaternary carbon atoms of the branched part by a stable ether bond, the structure of the heterobifunctional monodisperse polyethylene glycol In the chemical conversion process, it has a characteristic that it is difficult to decompose into single-chain monodisperse polyethylene glycol.
따라서, 본 발명은 하기의 것이다.Accordingly, the present invention is as follows.
[1] 식 (1)로 표시되는, 헤테로이관능성 단분산 폴리에틸렌 글리콜.[1] Heterodifunctional monodisperse polyethylene glycol represented by Formula (1).
(식 (1) 중, X1 및 Y1은 각각 생체기능성 분자에 존재하는 관능기와 반응하여 공유결합을 형성하는 관능기를 적어도 포함하는 원자단이며, 원자단 X1이 포함하는 상기 관능기와 원자단 Y1이 포함하는 상기 관능기는 서로 상이하고;(In Formula (1), X 1 and Y 1 are each an atomic group including at least a functional group that reacts with a functional group present in the biofunctional molecule to form a covalent bond, and the functional group and atomic group Y 1 included in the atomic group X 1 are The functional groups comprising are different from each other;
R1은 탄소수 1 내지 7의 탄화수소기 또는 수소 원자이고;R 1 is a hydrocarbon group having 1 to 7 carbon atoms or a hydrogen atom;
n은 3 내지 72의 정수이고;n is an integer from 3 to 72;
A1은 -L1-(CH2)m1-, -L1-(CH2)m1-L2-(CH2)m2- 또는 단결합을 나타내고, L1은 에테르 결합, 아미드 결합, 우레탄 결합, 2급 아미노기 또는 단결합을 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수를 나타내고;A 1 represents -L 1 -(CH 2 ) m1 -, -L 1 -(CH 2 ) m1 -L 2 -(CH 2 ) m2 - or a single bond, and L 1 represents an ether bond, an amide bond, or a urethane bond. , a secondary amino group or a single bond, L 2 represents an ether bond, an amide bond, or a urethane bond, m1 and m2 each independently represent an integer of 1 to 5;
B1은 -L3-(CH2)m3-, -L3-(CH2)m3-L4-(CH2)m4- 또는 단결합을 나타내고, L3은 아미드 결합 또는 단결합을 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수를 나타낸다.)B 1 represents -L 3 -(CH 2 ) m3 -, -L 3 -(CH 2 ) m3 -L 4 -(CH 2 ) m4 - or a single bond, L 3 represents an amide bond or a single bond, L 4 represents an ether bond, an amide bond, or a urethane bond, and m3 and m4 each independently represent an integer of 1 to 5.)
[2] [1]에 있어서, 식 (1) 중, A1은 -NHC(O)-(CH2)m1- 또는 -NHC(O)-(CH2)m1-L2-(CH2)m2-를 나타내고, B1은 -(CH2)m3- 또는 -(CH2)m3-L4-(CH2)m4-를 나타내는, 헤테로이관능성 단분산 폴리에틸렌 글리콜.[2] The method of [1], in formula (1), A 1 is -NHC(O)-(CH 2 ) m1 - or -NHC(O)-(CH 2 ) m1 -L 2 -(CH 2 ) Heterobifunctional monodisperse polyethylene glycol, wherein B 1 represents -(CH 2 ) m3 - or -(CH 2 ) m3 -L 4 -(CH 2 ) m4 -.
[3] [1]에 있어서, 식 (1) 중, A1은 -CH2- 또는 -CH2-L2-(CH2)m2-를 나타내고, B1은 -CH2- 또는 -CH2-L4-(CH2)m4-를 나타내는, 헤테로이관능성 단분산 폴리에틸렌 글리콜.[3] In [1], in formula (1), A 1 represents -CH 2 - or -CH 2 -L 2 -(CH 2 ) m2 -, and B 1 represents -CH 2 - or -CH 2 -L 4 -(CH 2 ) m4 -, heterobifunctional monodisperse polyethylene glycol.
[4] [1]에 있어서, 식 (1) 중, A1은 -O-(CH2)m1- 또는 -O-(CH2)m1-L2-(CH2)m2-를 나타내고, B1은 -CH2- 또는 -CH2-L4-(CH2)m4-를 나타내는, 헤테로이관능성 단분산 폴리에틸렌 글리콜.[4] In [1], in formula (1), A 1 represents -O-(CH 2 ) m1 - or -O-(CH 2 ) m1 -L 2 -(CH 2 ) m2 -, B 1 represents -CH 2 - or -CH 2 -L 4 -(CH 2 ) m4 -, heterobifunctional monodisperse polyethylene glycol.
[5] [1]에 있어서, 식 (1) 중, A1은 -C(O)NH-(CH2)m1- 또는 -C(O)NH-(CH2)m1-L2-(CH2)m2-를 나타내고, B1은 -CH2- 또는 -CH2-L4-(CH2)m4-를 나타내는, 헤테로이관능성 단분산 폴리에틸렌 글리콜.[5] The method of [1], in formula (1), A 1 is -C(O)NH-(CH 2 ) m1 - or -C(O)NH-(CH 2 ) m1 -L 2 -(CH 2 ) Heterobifunctional monodisperse polyethylene glycol, representing m2 - and B 1 representing -CH 2 - or -CH 2 -L 4 -(CH 2 ) m4 -.
[6] [1]에 있어서, 식 (1) 중, A1은 -C(O)NH-(CH2)m1- 또는 -C(O)NH-(CH2)m1-L2-(CH2)m2-를 나타내고, B1은 -C(O)NH-(CH2)m3- 또는 -C(O)NH-(CH2)m3-L4-(CH2)m4-를 나타내는, 헤테로이관능성 단분산 폴리에틸렌 글리콜.[6] The method of [1], in formula (1), A 1 is -C(O)NH-(CH 2 ) m1 - or -C(O)NH-(CH 2 ) m1 -L 2 -(CH 2 ) represents m2 -, B 1 represents -C(O)NH-(CH 2 ) m3 - or -C(O)NH-(CH 2 ) m3 -L 4 -(CH 2 ) m4 -, hetero Bifunctional monodisperse polyethylene glycol.
[7] [1] 내지 [6] 중 어느 하나에 있어서, 식 (1) 중 X1 및 Y1이, 각각 독립적으로 식 (a), 식 (b1), 식 (b2), 식 (c), 식 (d), 식 (e), 식 (f), 식 (g), 식 (h), 식 (i), 식 (j), 식 (k), 식 (l), 식 (m), 식 (n) 및 식 (o)로 구성되는 군으로부터 선택되는, 헤테로이관능성 단분산 폴리에틸렌 글리콜.[7] The method according to any one of [1] to [6], wherein in formula (1), X 1 and Y 1 are each independently formula (a), formula (b1), formula (b2), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), A heterobifunctional monodisperse polyethylene glycol selected from the group consisting of formula (j), formula (k), formula (l), formula (m), formula (n) and formula (o).
(식 (d) 중, R2는 수소 원자 또는 탄소수 1 내지 5의 탄화수소기이고;(in formula (d), R 2 is a hydrogen atom or a hydrocarbon group having 1 to 5 carbon atoms;
식 (e) 중, R3은 염소 원자, 브롬 원자 및 요오드 원자로부터 선택되는 할로겐 원자이고;In formula (e), R 3 is a halogen atom selected from a chlorine atom, a bromine atom and an iodine atom;
식 (l) 중, R4는 수소 원자 또는 탄소수 1 내지 5의 탄화수소기이다.)In formula (1), R 4 is a hydrogen atom or a hydrocarbon group having 1 to 5 carbon atoms.)
[8] 식 (2)로 표시되는, 헤테로이관능성 단분산 폴리에틸렌 글리콜을 포함하는 항체-약물 복합체.[8] An antibody-drug complex comprising a heterobifunctional monodisperse polyethylene glycol represented by Formula (2).
(식 (2) 중, X2 및 Y2 중 하나는 항체이고, 다른 하나는 약물이고;(in formula (2), one of X 2 and Y 2 is an antibody and the other is a drug;
R1은 탄소수 1 내지 7의 탄화수소기 또는 수소 원자이고;R 1 is a hydrocarbon group having 1 to 7 carbon atoms or a hydrogen atom;
n는 3 내지 72의 정수이고;n is an integer from 3 to 72;
A2은 -L1-(CH2)m1-L5-, -L1-(CH2)m1-L2-(CH2)m2-L5- 또는 단결합을 나타내고, L1은 에테르 결합, 아미드 결합, 우레탄 결합, 2급 아미노기 또는 단결합을 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수를 나타내고, L5는 아미드 결합, 우레탄 결합, 티오에테르 결합, 디술피드 결합, 카보네이트 결합, 에스테르 결합, 에테르 결합, 1H-1,2,3-트리아졸-1,4-디일 구조, 2급 아미노기, 히드라지드기, 옥시아미드기 또는 이들 중 어느 것을 포함하는 탄화수소기이고;A 2 represents -L 1 -(CH 2 ) m1 -L 5 -, -L 1 -(CH 2 ) m1 -L 2 -(CH 2 ) m2 -L 5 - or a single bond, L 1 is an ether bond , represents an amide bond, a urethane bond, a secondary amino group or a single bond, L 2 represents an ether bond, an amide bond or a urethane bond, m1 and m2 each independently represent an integer of 1 to 5, L 5 is an amide bond , urethane bond, thioether bond, disulfide bond, carbonate bond, ester bond, ether bond, 1H-1,2,3-triazole-1,4-diyl structure, secondary amino group, hydrazide group, oxyamide group or a hydrocarbon group containing any of these;
B2은 -L3-(CH2)m3-L6-, -L3-(CH2)m3-L4-(CH2)m4-L6- 또는 단결합을 나타내고, L3은 아미드 결합 또는 단결합을 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수를 나타내고, L6는 아미드 결합, 우레탄 결합, 티오에테르 결합, 디술피드 결합, 카보네이트 결합, 에스테르 결합, 에테르 결합, 1H-1,2,3-트리아졸-1,4-디일 구조, 2급 아미노기, 히드라지드기, 옥시아미드기 또는 이들 중 어느 것을 포함하는 탄화수소기이다.)B 2 represents -L 3 -(CH 2 ) m3 -L 6 -, -L 3 -(CH 2 ) m3 -L 4 -(CH 2 ) m4 -L 6 - or a single bond, and L 3 is an amide bond or a single bond, L 4 represents an ether bond, an amide bond, or a urethane bond, m3 and m4 each independently represent an integer of 1 to 5, L 6 is an amide bond, a urethane bond, a thioether bond, a disulfide a bond, a carbonate bond, an ester bond, an ether bond, a 1H-1,2,3-triazole-1,4-diyl structure, a secondary amino group, a hydrazide group, an oxyamide group, or a hydrocarbon group containing any of these .)
본 발명의 헤테로이관능성 단분산 폴리에틸렌 글리콜은 키랄 중심을 갖지 않기 때문에, 화학적 변환 공정에 있어서 키랄 중심에 원하지 않는 부분적인 입체 반전이나 라세미화의 문제가 근본적으로 발생하지 않고, 2개의 단분산 폴리에틸렌 글리콜 측쇄가 분기 부분의 4급 탄소 원자에 안정적인 에테르 결합으로 결합하고 있기 때문에, 화학적 변환 공정에 있어서 단일-사슬의 단분산 폴리에틸렌 글리콜로 분해하기 어렵다. 따라서, 당해 헤테로이관능성 단분산 폴리에틸렌 글리콜을 이용하여 항체와 약물을 결합하는 것으로써, 균질성이 높은 항체-약물 복합체를 얻을 수 있다.Since the heterobifunctional monodisperse polyethylene glycol of the present invention does not have a chiral center, the problem of partial steric inversion or racemization that is not desired at the chiral center in the chemical conversion process does not fundamentally occur, and two monodisperse polyethylene glycols Since the side chain is bonded to the quaternary carbon atom of the branched portion by a stable ether bond, it is difficult to decompose into a single-chain monodisperse polyethylene glycol in the chemical conversion process. Therefore, by binding the antibody and the drug using the heterobifunctional monodisperse polyethylene glycol, an antibody-drug complex with high homogeneity can be obtained.
또한, 당해 헤테로이관능성 단분산 폴리에틸렌 글리콜은, 2개의 단분산 폴리에틸렌 글리콜 측쇄가 서로 근접하여 결합하고 있기 때문에, 항체-약물 복합체를 제조하는 경우 소수성 약물의 차폐 효과가 크므로, 약물의 소수성에 기인하는 응집의 발생 또는 항체의 혈중 안정성의 저하를 억제할 수 있다.In addition, since the heterobifunctional monodisperse polyethylene glycol has a large shielding effect of the hydrophobic drug when preparing the antibody-drug complex, since two monodisperse polyethylene glycol side chains are closely bonded to each other, the hydrophobicity of the drug It is possible to suppress the occurrence of aggregation or a decrease in the blood stability of the antibody.
도 1은 실시예 8의 소수성 상호작용 크로마토그래피(HIC) 컬럼을 이용한 HPLC 측정의 차트이다.
도 2는 비교예 7의 소수성 상호작용 크로마토그래피 (HIC) 컬럼을 이용한 HPLC 측정의 차트이다.
도 3은 실시예 7로 얻은 식 (30)의 약물-링커 화합물에 대해서, 실시예 11의 소수성 상호작용 크로마토그래피(HIC) 컬럼을 이용한 HPLC 측정의 차트이다.
도 4는 비교예 6으로 얻은 식 (41)의 약물-링커 화합물에 대해서, 비교예 16의 소수성 상호작용 크로마토그래피(HIC) 컬럼을 이용한 HPLC 측정의 차트이다.
도 5는 비교예 15로 얻은 식 (47)의 약물-링커 화합물에 대해서, 비교예 17의 소수성 상호작용 크로마토그래피(HIC) 컬럼을 이용한 HPLC 측정의 차트이다.1 is a chart of HPLC measurements using the hydrophobic interaction chromatography (HIC) column of Example 8.
2 is a chart of HPLC measurement using a hydrophobic interaction chromatography (HIC) column of Comparative Example 7.
3 is a chart of HPLC measurement using the hydrophobic interaction chromatography (HIC) column of Example 11 for the drug-linker compound of Formula (30) obtained in Example 7. FIG.
4 is a chart of HPLC measurement using a hydrophobic interaction chromatography (HIC) column of Comparative Example 16 for the drug-linker compound of Formula (41) obtained in Comparative Example 6.
5 is a chart of HPLC measurement using a hydrophobic interaction chromatography (HIC) column of Comparative Example 17 for the drug-linker compound of Formula (47) obtained in Comparative Example 15. FIG.
이하, 본 발명을 상세하게 설명할 것이다.Hereinafter, the present invention will be described in detail.
본 명세서에 있어서의, "헤테로이관능성(heterobifunctional)"이란 용어는, 2개의 상이한 화학적 반응성 관능기들을 가지는 것을 의미하고, "단분산 폴리에틸렌 글리콜(monodispersed polyethylene glycol)"이란 용어는, 특정의 에틸렌글리콜 쇄장을 가지는 성분이 90% 이상 포함되는 화합물을 지칭한다. 또한, "키랄 중심을 갖지 않는다"는 용어는 거울상(mirror images)을 중첩할 수 있다는 것을 의미한다.As used herein, the term "heterobifunctional" means having two different chemically reactive functional groups, and the term "monodispersed polyethylene glycol" is a specific ethylene glycol chain length Refers to a compound in which 90% or more of a component having a Also, the term "having no chiral center" means that mirror images can be superimposed.
본 발명의 헤테로이관능성 단분산 폴리에틸렌 글리콜은 식 (1)로 표시된다.The heterobifunctional monodisperse polyethylene glycol of the present invention is represented by formula (1).
본 발명의 식 (1)에 있어서의 R1은 탄화수소기 또는 수소 원자이다. 탄화수소기의 탄소수는 7 이하가 바람직하다. 구체적인 탄화수소기의 예로서는 메틸기, 에틸기, 프로필기, 이소프로필기, 3차-부틸기, 페닐기 및 벤질기 등을 들 수 있다. R1의 바람직한 실시 형태는 메틸기 또는 수소 원자이며, 더욱 바람직하게는 메틸기이다.R< 1 > in Formula (1) of this invention is a hydrocarbon group or a hydrogen atom. As for carbon number of a hydrocarbon group, 7 or less are preferable. Specific examples of the hydrocarbon group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, a phenyl group, and a benzyl group. A preferred embodiment of R 1 is a methyl group or a hydrogen atom, and more preferably a methyl group.
본 발명의 식 (1)에 있어서의 n은, 단분산 폴리에틸렌 글리콜의 반복 단위 수를 나타내고, 3 내지 72의 정수이며, 바람직하게는 4 내지 48의 정수이며, 더욱 바람직하게는 6 내지 36의 정수이며, 특히 바람직하게는 8 내지 24의 정수이다.n in the formula (1) of the present invention represents the number of repeating units of monodisperse polyethylene glycol, and is an integer of 3-72, preferably an integer of 4-48, more preferably an integer of 6-36 and particularly preferably an integer of 8 to 24.
본 명세서에 있어서, 식 (1)의 원자단 X1 및 Y1은 서로 상이하고, 당해 헤테로이관능성 단분산 폴리에틸렌 글리콜에 의한 수식의 대상이 되는 생체기능성 분자(예를 들면, 생리 활성 단백질, 펩티드, 항체, 핵산 또는 저분자 약물 등)에 존재하는 관능기와 반응하여 공유결합을 형성하는 관능기를 적어도 포함하는 원자단이면 특히 제한되지 않는다. 상기 관능기의 예로서는 "Hermanson, G. T. Bioconjugate Techniques, 2nd ed.; Academic Press: San Diego, CA, 2008", "Harris, J. M. Poly(Ethylene Glycol) Chemistry; Plenum Press: New York, 1992", 및 "PEGylated Protein Drugs: Basic Science and Clinical Applications; Veronese, F. M., Ed.; Birkhauser: Basel, Switzerland, 2009" 등에 기재되어 있는 관능기를 들 수 있다.In the present specification, the atomic groups X 1 and Y 1 in Formula (1) are different from each other, and biofunctional molecules (eg, physiologically active proteins, peptides, It is not particularly limited as long as it is an atomic group including at least a functional group that reacts with a functional group present in an antibody, nucleic acid, or small molecule drug to form a covalent bond. Examples of such functional groups include "Hermanson, GT Bioconjugate Techniques, 2nd ed.; Academic Press: San Diego, CA, 2008", "Harris, JM Poly(Ethylene Glycol) Chemistry; Plenum Press: New York, 1992", and "PEGylated Protein" Drugs: Basic Science and Clinical Applications; Veronese, FM, Ed.; Birkhauser: Basel, Switzerland, 2009" and the like.
그 중에서도, X1 및 Y1에 포함되는 관능기는 각각 독립적으로, 단백질로 대표되는 천연의 생체 기능성 분자에 존재하는 관능기(예를 들면, 아미노기, 티올기, 알데히드기 또는 카르복실기) 또는 상기 전술한 생체기능성 분자에 인공적으로 도입가능한 관능기 (예를 들면, 말레이미드기, 케톤기, 아지드기 또는 알키닐기)에 온화한 반응 조건, 및 높은 반응 효율로 반응가능한 관능기인 것이 바람직하다. 보다 구체적으로는, 활성 에스테르기, 활성 카보네이트기, 알데히드기, 이소시아네이트기, 이소티오시아네이트기, 에폭시기, 말레이미드기, 비닐 술폰기, 아크릴기, 술포닐옥시기, 카르복시기, 티올기, 2-피리딜디티오기, α-할로아세틸기, 히드록시기, 알키닐기, 알릴기, 비닐기, 아미노기, 옥시아미노기, 히드라지드기, 아지드기 또는 디벤조시클로옥틴(DBCO)기가 바람직하다. 또한, 반응 효율을 고려하면, 활성 에스테르기, 활성 카보네이트기, 말레이미드기, α-할로아세틸기, 알키닐기, 아지드기 또는 디벤조시클로옥틴 (DBCO)기가 바람직하다.Among them, the functional groups included in X 1 and Y 1 are each independently a functional group (eg, an amino group, a thiol group, an aldehyde group or a carboxyl group) present in a natural biofunctional molecule represented by a protein or the above-mentioned biofunctionality. A functional group capable of reacting with a functional group artificially introduceable into a molecule (eg, maleimide group, ketone group, azide group or alkynyl group) under mild reaction conditions and with high reaction efficiency is preferable. More specifically, an active ester group, an active carbonate group, an aldehyde group, an isocyanate group, an isothiocyanate group, an epoxy group, a maleimide group, a vinyl sulfone group, an acryl group, a sulfonyloxy group, a carboxy group, a thiol group, 2-pyridyl A dithio group, α-haloacetyl group, hydroxyl group, alkynyl group, allyl group, vinyl group, amino group, oxyamino group, hydrazide group, azide group or dibenzocyclooctyne (DBCO) group is preferable. Further, in consideration of reaction efficiency, an active ester group, an active carbonate group, a maleimide group, an α-haloacetyl group, an alkynyl group, an azide group or a dibenzocyclooctyne (DBCO) group is preferable.
더욱 더 구체적으로는, X1 및 Y1에 포함되는 관능기는 각각 독립적으로, 수식의 대상이 되는 생체기능성 분자에 존재하는 관능기가 아미노기인 경우에는, 활성 에스테르기, 활성 카보네이트기, 알데히드기, 이소시아네이트기, 이소티오시아네이트기, 에폭시기, 말레이미드기, 비닐 술폰기, 아크릴기, 술포닐옥시기 또는 카르복시기이며; 수식의 대상이 되는 생체기능성 분자에 존재하는 관능기가 티올기인 경우에는, 활성 에스테르기, 활성 카보네이트기, 알데히드기, 이소시아네이트기, 이소티오시아네이트기, 에폭시기, 말레이미드기, 비닐 술폰기, 아크릴기, 술포닐옥시기, 카르복시기, 티올기, 2-피리딜디티오기, α-할로아세틸기, 알키닐기, 알릴기 또는 비닐기이며; 수식의 대상이 되는 생체 기능성 분자에 존재하는 관능기가 알데히드기 또는 카르복시기인 경우에는, 티올기, 히드록시기, 아미노기, 옥시아미노기 또는 히드라지드기이며; 수식의 대상이 되는 생체기능성 분자에 존재하는 관능기가 알키닐기인 경우에는, 티올기 또는 아지드기이며; 수식의 대상이 되는 생체기능성 분자에 존재하는 관능기가 아지드기인 경우에는, 알키닐기 또는 디벤조시클로옥틴기이며; 수식의 대상이 되는 생체기능성 분자에 존재하는 관능기가 할로겐화 알킬기, 알킬설폰산 에스테르 또는 아릴설폰산 에스테르인 경우에는, 티올기, 히드록시기 또는 아미노기이다.More specifically, the functional groups included in X 1 and Y 1 are each independently an active ester group, an active carbonate group, an aldehyde group, and an isocyanate group when the functional group present in the biofunctional molecule to be modified is an amino group. , an isothiocyanate group, an epoxy group, a maleimide group, a vinyl sulfone group, an acryl group, a sulfonyloxy group or a carboxy group; When the functional group present in the biofunctional molecule to be modified is a thiol group, an active ester group, an active carbonate group, an aldehyde group, an isocyanate group, an isothiocyanate group, an epoxy group, a maleimide group, a vinyl sulfone group, an acrylic group, a sulfonyloxy group, a carboxy group, a thiol group, a 2-pyridyldithio group, an α-haloacetyl group, an alkynyl group, an allyl group or a vinyl group; When the functional group present in the biofunctional molecule to be modified is an aldehyde group or a carboxy group, it is a thiol group, a hydroxyl group, an amino group, an oxyamino group, or a hydrazide group; When the functional group present in the biofunctional molecule to be modified is an alkynyl group, it is a thiol group or an azide group; When the functional group present in the biofunctional molecule to be modified is an azide group, it is an alkynyl group or a dibenzocyclooctyne group; When the functional group present in the biofunctional molecule to be modified is a halogenated alkyl group, alkylsulfonic acid ester or arylsulfonic acid ester, it is a thiol group, a hydroxyl group or an amino group.
본원에서의 용어 "활성 에스테르기"란, 식: -C(=O)-L로 표시되는 활성화된 카르복시기를 나타내고, 여기서 L은 이탈기를 나타낸다. L로 표시되는 이탈기로서는, 숙신이미딜옥시기, 프탈이미딜옥시기, 4-니트로페녹시기, 1-이미다졸릴기, 펜타플루오로페녹시기, 벤조트리아졸-1-일옥시기, 7-아자벤조트리아졸-1-일옥시기 등을 들 수 있다. 본원에서의 용어 "활성 카보네이트"란, 식: -O-C(=O)-L로 표시되는 활성화된 카보네이트기를 나타내고, 여기서 L은 상기와 같은 이탈기를 나타낸다.The term "active ester group" herein refers to an activated carboxy group represented by the formula: -C(=O)-L, where L represents a leaving group. As the leaving group represented by L, succinimidyloxy group, phthalimidyloxy group, 4-nitrophenoxy group, 1-imidazolyl group, pentafluorophenoxy group, benzotriazol-1-yloxy group, 7-azabenzo A triazol-1-yloxy group etc. are mentioned. As used herein, the term "active carbonate" refers to an activated carbonate group represented by the formula: -O-C(=O)-L, where L represents a leaving group as described above.
본 발명의 바람직한 실시 형태에 있어서, X1 및 Y1은 각각 독립적으로, 군 (I), 군 (II), 군 (III), 군 (IV), 군 (V) 또는 군 (VI)으로 표시되는 기이다.In a preferred embodiment of the present invention, X 1 and Y 1 are each independently represented by group (I), group (II), group (III), group (IV), group (V) or group (VI). It is a period of becoming
군 (I): 생체기능성 분자의 아미노기와 반응하여 공유 결합을 형성하는 것이 가능한 관능기로Group (I): functional groups capable of reacting with amino groups of biofunctional molecules to form covalent bonds
하기의 (a), (b1), (b2), (c), (d), (e) 및 (f):(a), (b1), (b2), (c), (d), (e) and (f):
군 (II): 생체기능성 분자의 티올기와 반응하여 공유 결합을 형성하는 것이 가능한 관능기로Group (II): functional groups capable of reacting with thiol groups of biofunctional molecules to form covalent bonds
하기의 (a), (b1), (b2), (c), (d), (e), (f), (g), (h) 및 (l): (a), (b1), (b2), (c), (d), (e), (f), (g), (h) and (l):
군 (III): 생체기능성 분자의 알데히드기 또는 카르복시기와 반응하여 공유 결합을 형성하는 것이 가능한 관능기로Group (III): a functional group capable of forming a covalent bond by reacting with an aldehyde group or a carboxyl group of a biofunctional molecule
하기의 (g), (i), (j), (k) 및 (o):(g), (i), (j), (k) and (o) of:
군 (IV): 생체기능성 분자의 알키닐기와 반응하여 공유 결합을 형성하는 것이 가능한 관능기로Group (IV): a functional group capable of forming a covalent bond by reacting with an alkynyl group of a biofunctional molecule
하기의 (g), (i), (j), (k) 및 (n):(g), (i), (j), (k) and (n) of:
군 (V): 생체기능성 분자의 아지드기와 반응하여 공유 결합을 형성하는 것이 가능한 관능기로Group (V): a functional group capable of forming a covalent bond by reacting with an azide group of a biofunctional molecule
하기의 (l) 및 (m):(l) and (m) of:
군 (VI): 생체기능성 분자의 할로겐화 알킬기, 알킬설폰산 에스테르 또는 아릴설폰산 에스테르와 반응하여 공유 결합을 형성하는 것이 가능한 관능기로Group (VI): functional groups capable of forming covalent bonds by reacting with halogenated alkyl groups, alkylsulfonic acid esters or arylsulfonic acid esters of biofunctional molecules
하기의 (g), (i) 및 (o):(g), (i) and (o) of:
상기 식 중, R2 및 R4는 각각 수소 원자 또는 탄소수 1 내지 5의 탄화수소기이며, 구체적인 탄화수소기의 예로서는 메틸기, 에틸기, 프로필기, 이소프로필기, 부틸기, 3차-부틸기 및 펜틸기 등을 들 수 있다. R3은 염소 원자, 브롬 원자 및 요오드 원자로부터 선택되는 할로겐 원자이다.In the above formula, R 2 and R 4 are each a hydrogen atom or a hydrocarbon group having 1 to 5 carbon atoms, and specific examples of the hydrocarbon group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group and a pentyl group. and the like. R 3 is a halogen atom selected from a chlorine atom, a bromine atom and an iodine atom.
식 (1) 중의 원자단 X1 및 Y1에 포함되는 관능기의 조합의 바람직한 예로서, X1에 포함되는 관능기가 활성 에스테르기 또는 활성 카보네이트기인 경우, Y1에 포함되는 관능기는 말레이미드기, 비닐 술폰기, α-할로아세틸기, 알키닐기 및 아지드기로부터 선택되는 기이며; X1에 포함되는 관능기가 알데히드기인 경우, Y1에 포함되는 관능기는 말레이미드기, 비닐 술폰기, 알키닐기 및 아지드기로부터 선택되는 기이며; X1에 포함되는 관능기가 말레이미드기, 비닐 술폰기 또는 α-할로아세틸기인 경우, Y1에 포함되는 관능기는 활성 에스테르기, 활성 카보네이트기, 알키닐기 및 아지드기로부터 선택되는 기이며; X1에 포함되는 관능기가 알키닐기 또는 아지드기인 경우, Y1에 포함되는 관능기는 말레이미드기, 비닐 술폰기, α-할로아세틸기, 활성 에스테르기, 활성 카보네이트기, 아미노기, 옥시아미노기 및 히드록시기로부터 선택되는 기이며; X1에 포함되는 관능기가 아미노기 또는 옥시아미노기인 경우, Y1에 포함되는 관능기는 알키닐기, 아지드기, 티올기, 히드록시기 및 카르복시기로부터 선택되는 기이며; X1에 포함되는 관능기가 티올기, 2-피리딜디티오기 또는 히드록시기인 경우, Y1은 아미노기, 옥시아미노기, 아지드기 및 카르복시기로부터 선택되는 기이다. 더욱 바람직하게는, X1에 포함되는 관능기가 활성 에스테르기 또는 활성 카보네이트기인 경우, Y1에 포함되는 관능기는 말레이미드기, α-할로아세틸기, 알키닐기 및 아지드기로부터 선택되는 기이며; X1에 포함되는 관능기가 알데히드기인 경우, Y1에 포함되는 관능기는 말레이미드기, α-할로아세틸기, 알키닐기 및 아지드기로부터 선택되는 기이며; X1에 포함되는 관능기가 말레이미드기 또는 α-할로아세틸기인 경우, Y1에 포함되는 관능기는 활성 에스테르기, 활성 카보네이트기, 알키닐기 및 아지드기로부터 선택되는 기이며; X1에 포함되는 관능기가 알키닐기 또는 아지드기인 경우, Y1에 포함되는 관능기는 말레이미드기, α-할로아세틸기, 활성 에스테르기, 활성 카보네이트기, 아미노기, 옥시아미노기 및 히드록시기로부터 선택되는 기이며; X1에 포함되는 관능기가 아미노기 또는 옥시아미노기인 경우, Y1에 포함되는 관능기는 알키닐기, 아지드기, 히드록시기 및 티올기로부터 선택되는 기이며; X1에 포함되는 관능기가 티올기, 2-피리딜디티오기 또는 히드록시기인 경우, Y1에 포함되는 관능기는 아미노기, 옥시아미노기 및 아지드기로부터 선택되는 기이다.As a preferred example of a combination of the functional groups contained in the atomic groups X 1 and Y 1 in Formula (1), when the functional group contained in X 1 is an active ester group or an active carbonate group, the functional group contained in Y 1 is a maleimide group, vinyl a group selected from a sulfone group, an α-haloacetyl group, an alkynyl group and an azide group; When the functional group included in X 1 is an aldehyde group, the functional group included in Y 1 is a group selected from a maleimide group, a vinyl sulfone group, an alkynyl group, and an azide group; When the functional group included in X 1 is a maleimide group, a vinyl sulfone group or an α-haloacetyl group, the functional group included in Y 1 is a group selected from an active ester group, an active carbonate group, an alkynyl group and an azide group; When the functional group included in X 1 is an alkynyl group or an azide group, the functional group included in Y 1 is a maleimide group, a vinyl sulfone group, an α-haloacetyl group, an active ester group, an active carbonate group, an amino group, an oxyamino group, and a hydroxyl group. is a group selected from; When the functional group included in X 1 is an amino group or an oxyamino group, the functional group included in Y 1 is a group selected from an alkynyl group, an azide group, a thiol group, a hydroxy group, and a carboxy group; When the functional group included in X 1 is a thiol group, a 2-pyridyldithio group or a hydroxy group, Y 1 is a group selected from an amino group, an oxyamino group, an azide group, and a carboxy group. More preferably, when the functional group contained in X 1 is an active ester group or an active carbonate group, the functional group contained in Y 1 is a group selected from a maleimide group, an α-haloacetyl group, an alkynyl group and an azide group; When the functional group included in X 1 is an aldehyde group, the functional group included in Y 1 is a group selected from a maleimide group, an α-haloacetyl group, an alkynyl group and an azide group; When the functional group included in X 1 is a maleimide group or an α-haloacetyl group, the functional group included in Y 1 is a group selected from an active ester group, an active carbonate group, an alkynyl group and an azide group; When the functional group included in X 1 is an alkynyl group or an azide group, the functional group included in Y 1 is a group selected from a maleimide group, an α-haloacetyl group, an active ester group, an active carbonate group, an amino group, an oxyamino group, and a hydroxyl group. is; When the functional group included in X 1 is an amino group or an oxyamino group, the functional group included in Y 1 is a group selected from an alkynyl group, an azide group, a hydroxyl group, and a thiol group; When the functional group included in X 1 is a thiol group, a 2-pyridyldithio group or a hydroxy group, the functional group included in Y 1 is a group selected from an amino group, an oxyamino group, and an azide group.
본 발명의 식 (1)에서의 A1은, 분기 부분의 4급 탄소 원자와 X1과의 사이의 2가의 스페이서(divalent spacer)이고, 식 (1)에서의 B1은, 분기 부분의 4급 탄소 원자와 Y1과의 사이의 2가의 스페이서이며, 이들은 각각 공유결합으로 구성된다. 구체적으로는, A1은 -L1-(CH2)m1-, -L1-(CH2)m1-L2-(CH2)m2- 또는 단결합을 나타내고, L1은 에테르 결합, 아미드 결합, 우레탄 결합, 2급 아미노기 또는 단결합을 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수를 나타낸다. 또한, B1은 -L3-(CH2)m3-, -L3-(CH2)m3-L4-(CH2)m4- 또는 단결합을 나타내고, L3은 아미드 결합 또는 단결합을 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수를 나타낸다.A 1 in the formula (1) of the present invention is a divalent spacer between the quaternary carbon atom of the branched moiety and X 1 , and B 1 in the formula (1) is 4 of the branched moiety. It is a divalent spacer between a primary carbon atom and Y< 1 >, and these are each comprised by a covalent bond. Specifically, A 1 represents -L 1 -(CH 2 ) m1 -, -L 1 -(CH 2 ) m1 -L 2 -(CH 2 ) m2 - or a single bond, and L 1 represents an ether bond, an amide A bond, a urethane bond, a secondary amino group, or a single bond is represented, L 2 is an ether bond, an amide bond or a urethane bond, and m1 and m2 each independently represent an integer of 1 to 5. In addition, B 1 represents -L 3 -(CH 2 ) m3 -, -L 3 -(CH 2 ) m3 -L 4 -(CH 2 ) m4 - or a single bond, and L 3 represents an amide bond or a single bond. L 4 represents an ether bond, an amide bond or a urethane bond, and m3 and m4 each independently represent an integer of 1 to 5.
본 발명의 바람직한 실시 형태에 있어서의 식 (1) 중의 A1 및 B1의 구체적인 구조, 및 상기 전술한 A1 및 B1을 가지는 헤테로이관능성 단분산 폴리에틸렌 글리콜의 전형적인 합성예를 이하에 설명하지만, 본 발명은 이것으로 한정되는 것은 아니다.Specific structures of A 1 and B 1 in Formula (1) in a preferred embodiment of the present invention, and typical synthesis examples of heterobifunctional monodisperse polyethylene glycol having the above-mentioned A 1 and B 1 will be described below. , the present invention is not limited thereto.
(A) 본 발명의 바람직한 실시 형태에 있어서, 식 (1)에서의 A1이 -NHC(O)-(CH2)m1- 또는 -NHC(O)-(CH2)m1-L2-(CH2)m2-로 나타내어지고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합이고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수이며, B1이 -(CH2)m3- 또는 -(CH2)m3-L4-(CH2)m4-로 나타내어지고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합이고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수이다. 더욱 바람직하게는, A1이 -NHC(O)-(CH2)m1-로 나타내어지고, m1은 1 내지 5의 정수이며, B1이 -(CH2)m3- 또는 -(CH2)m3-O-(CH2)m4-로 나타내어지고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수이다.(A) In a preferred embodiment of the present invention, A 1 in formula (1) is -NHC(O)-(CH 2 ) m1- or -NHC(O)-(CH 2 ) m1 -L 2 -( CH 2 ) represented by m2 -, L 2 is an ether bond, an amide bond, or a urethane bond, m1 and m2 are each independently an integer of 1 to 5, B 1 is -(CH 2 ) m3 - or -(CH 2 ) It is represented by m3 -L 4 -(CH 2 ) m4 -, L 4 is an ether bond, an amide bond, or a urethane bond, and m3 and m4 are each independently an integer of 1 to 5. More preferably, A 1 is represented by -NHC(O)-(CH 2 ) m1 -, m1 is an integer from 1 to 5, and B 1 is -(CH 2 ) m3 - or -(CH 2 ) m3 It is represented by -O-(CH 2 ) m4 -, and m3 and m4 are each independently an integer of 1 to 5.
상기 전술한 헤테로이관능성 단분산 폴리에틸렌 글리콜을 합성하는 전형적인 예로서는, 이하의 공정을 들 수 있다. 여기에서는, 관능기로서 말레이미드기 및 p-니트로페닐 카보네이트기를 도입한 화합물에 대하여 예시한다.Typical examples of synthesizing the above-mentioned heterobifunctional monodisperse polyethylene glycol include the following steps. Here, the compounds in which a maleimide group and a p-nitrophenyl carbonate group are introduced as functional groups are exemplified.
(식 (3) 중, P1은 아미노기의 보호기이며, P2는 히드록시기의 보호기이다.)(In formula (3), P 1 is a protecting group of an amino group, and P 2 is a protecting group of a hydroxyl group.)
상기 식 (3)에서 나타내어지는 화합물을 무수 용매 중, 강염기 존재 하에서 모노메틸 단분산 폴리에틸렌 글리콜의 알킬 또는 아릴 술폰산 에스테르, 또는 모노메틸 단분산 폴리에틸렌 글리콜의 할로겐화물에 대해서 친핵성 치환 반응을 겪게하고, 하기 식 (4)에서 나타내어지는 화합물을 얻는다.subjecting the compound represented by the formula (3) to a nucleophilic substitution reaction for an alkyl or aryl sulfonic acid ester of monomethyl monodisperse polyethylene glycol or a halide of monomethyl monodisperse polyethylene glycol in an anhydrous solvent in the presence of a strong base; A compound represented by the following formula (4) is obtained.
본원에서 지칭되는 것으로 "보호기"란, 어떤 반응 조건 하에서 분자 중의 특정 관능기의 반응을 방지 또는 저지하는 성분이다. 상기 보호기는, 보호되는 관능기의 종류, 사용되는 조건 및 분자 중의 다른 관능기 또는 보호기의 존재에 따라 변화한다. 보호기의 구체적인 예들은 많은 일반적인 성서에 찾아볼 수 있지만, 예를 들면, "Wuts, P. G M.; Greene, T. W. Protective Groups in Organic Synthesis, 4th ed.; Wiley-Interscience: New York, 2007"에 기재되어 있다. 또한, 보호기로 보호되는 관능기는, 각각의 보호기로 적합한 반응 조건을 이용하여 탈보호, 즉 화학 반응시키는 것으로, 원래의 관능기를 재생시킬 수 있다. 보호기의 대표적인 탈보호 조건은 전술의 문헌에 기재되어 있다.A "protecting group" as referred to herein is a component that prevents or prevents the reaction of a specific functional group in a molecule under certain reaction conditions. The protecting group changes depending on the type of the functional group to be protected, the conditions used, and the presence of other functional groups or protecting groups in the molecule. Specific examples of protecting groups can be found in many general biblical texts, but, for example, in "Wuts, P. G M.; Greene, T. W. Protective Groups in Organic Synthesis, 4th ed.; Wiley-Interscience: New York, 2007" is described. In addition, the functional group protected by the protecting group can be deprotected, ie, chemically reacted, using suitable reaction conditions for each protecting group, so that the original functional group can be regenerated. Exemplary deprotection conditions for protecting groups are described in the literature above.
보호되는 관능기와 보호기의 바람직한 조합으로서는 보호되는 관능기가 아미노기인 경우, 예를 들면 아실계 보호기 및 카바메이트계 보호기를 들 수 있고, 이들의 구체적인 예로는 트리플루오로아세틸기, 9-플루오레닐메틸옥시카르보닐기 및 2-(트리메틸실릴)에틸옥시카르보닐기 등을 들 수 있다. 또한, 보호되는 관능기가 히드록시기인 경우, 예를 들면 실릴계 보호기 및 아실계 보호기를 들 수 있고, 이들의 구체적인 예로는 3차-부틸디페닐실릴기, 3차-부틸디메틸실릴기, 트리이소프로필실릴기, 아세틸기 및 피발로일기 등을 들 수 있다.As a preferable combination of the functional group to be protected and the protecting group, when the functional group to be protected is an amino group, for example, an acyl protecting group and a carbamate protecting group are exemplified, and specific examples thereof include a trifluoroacetyl group and 9-fluorenylmethyl group. An oxycarbonyl group, 2-(trimethylsilyl)ethyloxycarbonyl group, etc. are mentioned. In addition, when the functional group to be protected is a hydroxyl group, for example, a silyl-based protecting group and an acyl-based protecting group may be mentioned, and specific examples thereof include a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, and triisopropyl. A silyl group, an acetyl group, a pivaloyl group, etc. are mentioned.
보호되는 관능기가 카르복시기인 경우, 예를 들면 알킬 에스테르계 보호기 및 실릴 에스테르계 보호기를 들 수 있고, 이들의 구체적인 예로는 메틸기, 9-플루오레닐메틸기 및 3차-부틸디메틸실릴기 등을 들 수 있다. 보호되는 관능기가 술파닐기인 경우, 예를 들면 티오에테르계 보호기, 티오카보네이트계 보호기 및 디술피드계 보호기를 들 수 있고, 이들의 구체적인 예로는 S-2,4-디니트로페닐기, S-9-플루오레닐메틸옥시카르보닐기 및 S-3차-부틸디술피드기 등을 들 수 있다. 또한, 동종 또는 이종의 2개의 관능기를 동시에 보호하는 것이 가능한 이관능성의 보호기를 이용할 수도 있다. 보호되는 관능기와 보호기의 바람직한 조합으로서는 보호되는 관능기가 2개의 히드록시기인 경우, 예를 들면 환상 아세탈계 보호기 및 환상 실릴계 보호기를 들 수 있고, 이들의 구체적인 예로는 2,2-디메틸-1,3-디옥솔란기, 2,2-디메틸-1,3-디옥산기, 2-페닐-1,3-디옥솔란기, 2-페닐-1,3-디옥산기 및 디-3차-부틸실릴렌기 등을 들 수 있다. 보호되는 관능기가 아미노기와 히드록시기인 경우, 예를 들면, 옥사졸린계 보호기를 들 수 있고, 이들의 구체적인 예로는 2-페닐옥사졸린기 등을 들 수 있다.When the functional group to be protected is a carboxy group, for example, an alkyl ester protecting group and a silyl ester protecting group may be mentioned, and specific examples thereof include a methyl group, 9-fluorenylmethyl group, and tert-butyldimethylsilyl group. have. When the functional group to be protected is a sulfanyl group, for example, a thioether-based protecting group, a thiocarbonate-based protecting group, and a disulfide-based protecting group may be mentioned, and specific examples thereof include S-2,4-dinitrophenyl group, S-9- and a fluorenylmethyloxycarbonyl group and an S-tert-butyldisulfide group. In addition, it is also possible to use a bifunctional protecting group capable of protecting two functional groups of the same type or of a different type at the same time. As a preferable combination of the functional group to be protected and the protecting group, when the functional group to be protected is two hydroxy groups, for example, a cyclic acetal protecting group and a cyclic silyl protecting group are exemplified, and specific examples thereof include 2,2-dimethyl-1,3 -dioxolane group, 2,2-dimethyl-1,3-dioxane group, 2-phenyl-1,3-dioxolane group, 2-phenyl-1,3-dioxane group and di-tert-butylsilyl Rengi etc. are mentioned. When the functional group to be protected is an amino group and a hydroxyl group, for example, an oxazoline-based protecting group may be used, and specific examples thereof may include a 2-phenyloxazoline group.
보호기의 대표적인 탈보호 조건은 전술의 문헌에 기재되어 있으며, 각각의 보호기로 적합한 반응 조건을 선택할 수 있다. 그러나, 구조 중에 포함되는 관능기가, 보호기로 보호되어 있지 않아도 다른 관능기의 화학 반응을 저해하지 않는 관능기의 경우는, 보호기를 사용할 필요는 없다.Representative deprotection conditions of the protecting group are described in the above literature, and suitable reaction conditions for each protecting group can be selected. However, in the case of a functional group that does not inhibit the chemical reaction of other functional groups even if the functional group contained in the structure is not protected by a protecting group, it is not necessary to use a protecting group.
상기 식 (4)에서 나타내어지는 화합물의 보호기 P1을 탈보호한 후, 얻어진 화합물을 축합제의 존재 하에, 6-말레이미도헥사노익산과 반응시키고, 하기 식 (5)에서 나타내어지는 화합물을 얻는다. 여기서, 히드록시기가 아미노기의 반응 시약과 반응하지 않는 반응 조건을 선택하는 경우, 보호기 P1과 동시에 보호기 P2도 탈보호될 수 있다.After deprotecting the protecting group P 1 of the compound represented by the formula (4), the obtained compound is reacted with 6-maleimidohexanoic acid in the presence of a condensing agent to obtain a compound represented by the following formula (5) . Here, when a reaction condition in which the hydroxyl group does not react with the reaction reagent of the amino group is selected, the protecting group P 1 and the protecting group P 2 may also be deprotected.
상기 식 (5)에서 나타내어지는 화합물의 보호기 P2를 탈보호한 후, 얻어진 화합물을 염기의 존재 하에, p-니트로페닐 클로로포르메이트와 반응시키고, 하기 식 (6)에서 나타내어지는 화합물을 얻는다.After deprotecting the protecting group P 2 of the compound represented by the formula (5), the obtained compound is reacted with p-nitrophenyl chloroformate in the presence of a base to obtain a compound represented by the following formula (6).
(B) 본 발명의 바람직한 다른 실시 형태에 있어서는, 식 (1) 중의 A1은 -CH2- 또는 -CH2-L2-(CH2)m2-를 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합이고, m2는 1 내지 5의 정수이며, B1은 -CH2- 또는 -CH2-L4-(CH2)m4-를 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합이고, m4는 1 내지 5의 정수이다. 더욱 바람직하게는, A1은 -CH2-NHC(O)-(CH2)m2-를 나타내고, m2는 1 내지 5의 정수이며, B1은 -CH2- 또는 -CH2-O-(CH2)m4-로 나타내고, m4는 1 내지 5의 정수이다.(B) In another preferred embodiment of the present invention, A 1 in formula (1) represents -CH 2 - or -CH 2 -L 2 -(CH 2 ) m2 -, and L 2 represents an ether bond or an amide bond. or a urethane bond, m2 is an integer of 1 to 5, B 1 represents -CH 2 - or -CH 2 -L 4 -(CH 2 ) m4 -, L 4 is an ether bond, an amide bond or a urethane bond; , m4 is an integer from 1 to 5; More preferably, A 1 represents -CH 2 -NHC(O)-(CH 2 ) m2 -, m2 is an integer from 1 to 5, and B 1 is -CH 2 - or -CH 2 -O-( CH 2 ) It is represented by m4 -, and m4 is an integer of 1 to 5.
상기 헤테로이관능성 단분산 폴리에틸렌 글리콜을 합성하는 전형적인 예로서는, 이하의 공정을 들 수 있다. 여기에서는, 관능기로서 요오드아세트아미드기 및 N-숙신이미딜 에스테르기를 도입한 화합물에 대하여 예시한다.Typical examples of synthesizing the heterobifunctional monodisperse polyethylene glycol include the following steps. Here, as a functional group, the compound which introduce|transduced the iodine acetamide group and N-succinimidyl ester group is illustrated.
(식 (7) 중, P3은 아미노기의 보호기이고, P4는 히드록시기의 보호기이다.)(In formula (7), P 3 is a protecting group of an amino group, and P 4 is a protecting group of a hydroxyl group.)
상기 식 (7)에서 나타내어지는 화합물을 무수 용매 중, 강염기 존재 하에서 모노메틸 단분산 폴리에틸렌 글리콜의 알킬 또는 아릴 술폰산 에스테르, 또는 모노메틸 단분산 폴리에틸렌 글리콜의 할로겐화물에 대해서 친핵성 치환 반응을 겪게하고, 하기 식 (8)에서 나타내어지는 화합물을 얻는다. The compound represented by the formula (7) is subjected to a nucleophilic substitution reaction for an alkyl or aryl sulfonic acid ester of monomethyl monodisperse polyethylene glycol or a halide of monomethyl monodisperse polyethylene glycol in an anhydrous solvent in the presence of a strong base, A compound represented by the following formula (8) is obtained.
상기 식 (8)에서 나타내어지는 화합물의 보호기 P4를 탈보호한 후, 무수 용매중, 염기의 존재 하에서, 4-히드록시부탄산의 카르복시기-보호체와 반응시키고, 하기 식 (9)에서 나타내어지는 화합물을 얻는다.After deprotecting the protecting group P 4 of the compound represented by the formula (8), it is reacted with a carboxyl-protecting body of 4-hydroxybutanoic acid in an anhydrous solvent in the presence of a base, and is represented by the following formula (9) losing compounds.
(식 중, P5는 카르복시기의 보호기이다.)(Wherein, P 5 is a protecting group of a carboxy group.)
상기 식 (9)에서 나타내어지는 화합물의 보호기 P3을 탈보호한 후, 요오드아세트산 무수물과 반응시키고, 하기 식 (10)에서 나타내어지는 화합물을 얻는다.After deprotecting the protecting group P 3 of the compound represented by the formula (9), it is reacted with iodoacetic anhydride to obtain a compound represented by the following formula (10).
상기 식 (10)에서 나타내어지는 화합물의 보호기 P5를 탈보호한 후, 축합제의 존재 하에서, N-히드록시숙신이미드와 반응시키고, 하기 식 (11)에서 나타내어지는 화합물을 얻는다.After deprotecting the protecting group P 5 of the compound represented by the formula (10), it is reacted with N-hydroxysuccinimide in the presence of a condensing agent to obtain a compound represented by the following formula (11).
(C) 본 발명의 더욱 바람직한 다른 실시 형태에 있어서는, 식 (1) 중의 A1은 -O-(CH2)m1- 또는 -O-(CH2)m1-L2-(CH2)m2-를 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합이고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수이며, B1은 -CH2- 또는 -CH2-L4-(CH2)m4-를 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합이고, m4는 1 내지 5의 정수이다. 더욱 바람직하게는, A1은 -O-(CH2)m1-NHC(O)-(CH2)m2-를 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수이고, B1은 -CH2- 또는 -CH2-O-(CH2)m4-를 나타내고 m4는 1 내지 5의 정수이다.(C) In another more preferred embodiment of the present invention, A 1 in formula (1) is -O-(CH 2 ) m1 - or -O-(CH 2 ) m1 -L 2 -(CH 2 ) m2 - represents, L 2 is an ether bond, an amide bond, or a urethane bond, m1 and m2 are each independently an integer of 1 to 5, B 1 is -CH 2 - or -CH 2 -L 4 -(CH 2 ) m4 represents -, L 4 is an ether bond, an amide bond, or a urethane bond, and m4 is an integer of 1 to 5. More preferably, A 1 represents -O-(CH 2 ) m1 -NHC(O)-(CH 2 ) m2 -, m1 and m2 are each independently an integer from 1 to 5, and B 1 is —CH 2 - or -CH 2 -O-(CH 2 ) m4 -, and m4 is an integer of 1 to 5.
상기 헤테로이관능성 단분산 폴리에틸렌 글리콜을 합성하는 전형적인 예로서는, 이하의 공정을 들 수 있다. 여기에서는, 관능기로서 2-피리딜디티오기 및 N-숙신이미딜 카보네이트기를 도입한 화합물에 대하여 예시한다.Typical examples of synthesizing the heterobifunctional monodisperse polyethylene glycol include the following steps. Here, as a functional group, the compound into which the 2-pyridyl dithio group and N-succinimidyl carbonate group were introduce|transduced is illustrated.
(식 (12) 중, P6은 아미노기의 보호기이고, P7은 히드록시기의 보호기이다.)(In formula (12), P 6 is a protecting group of an amino group, and P 7 is a protecting group of a hydroxyl group.)
상기 식 (12)에서 나타내어지는 화합물을 무수 용매 중, 강염기 존재 하에서 모노메틸 단분산 폴리에틸렌 글리콜의 알킬 또는 아릴 술폰산 에스테르, 또는 모노메틸 단분산 폴리에틸렌 글리콜의 할로겐화물에 대해서 친핵성 치환 반응을 겪게하고, 하기 식 (13)에서 나타내어지는 화합물을 얻는다.subjecting the compound represented by the formula (12) to a nucleophilic substitution reaction for an alkyl or aryl sulfonic acid ester of monomethyl monodisperse polyethylene glycol or a halide of monomethyl monodisperse polyethylene glycol in an anhydrous solvent in the presence of a strong base; A compound represented by the following formula (13) is obtained.
상기 식 (13)에서 나타내어지는 화합물의 보호기 P6을 탈보호한 후, 얻어진 화합물을 N-숙신이미딜 3-(2-피리딜디티오)프로피온산과 반응시키고, 하기 식 (14)에서 나타내어지는 화합물을 얻는다.After deprotecting the protecting group P 6 of the compound represented by the formula (13), the obtained compound is reacted with N-succinimidyl 3-(2-pyridyldithio)propionic acid, and the compound represented by the following formula (14) is get the compound.
상기 식 (14)에서 나타내어지는 화합물의 보호기 P7을 탈보호한 후, 염기의 존재 하에서, 얻어진 화합물을 N,N-디숙신이미딜 카보네이트와 반응시키고, 하기 식 (15)에서 나타내어지는 화합물을 얻는다.After deprotecting the protecting group P 7 of the compound represented by the formula (14), in the presence of a base, the obtained compound is reacted with N,N-disuccinimidyl carbonate to obtain a compound represented by the following formula (15) get
(D) 본 발명의 더욱 바람직한 다른 실시 형태에 있어서는, 식 (1)의 A1은 -C(O)NH-(CH2)m1- 또는 -C(O)NH-(CH2)m1-L2-(CH2)m2-를 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합이고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수이며, B1은 -CH2- 또는 -CH2-L4-(CH2)m4-를 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합이고, m4는 1 내지 5의 정수이다. 더욱 바람직하게는, A1은 -C(O)NH-(CH2)m1-를 나타내고, m1은 1 내지 5의 정수이고, B1은 -CH2- 또는 -CH2-O-(CH2)m4-를 나타내고 m4는 1 내지 5의 정수이다.(D) In another preferred embodiment of the present invention, A 1 in formula (1) is -C(O)NH-(CH 2 ) m1- or -C(O)NH-(CH 2 ) m1 -L 2 -(CH 2 ) m2 - is represented, L 2 is an ether bond, an amide bond or a urethane bond, m1 and m2 are each independently an integer of 1 to 5, B 1 is -CH 2 - or -CH 2 - L 4 -(CH 2 ) m4 - is represented, L 4 is an ether bond, an amide bond or a urethane bond, and m4 is an integer of 1 to 5. More preferably, A 1 represents -C(O)NH-(CH 2 ) m1 -, m1 is an integer from 1 to 5, and B 1 is -CH 2 - or -CH 2 -O-(CH 2 ) ) m4 - and m4 is an integer of 1 to 5.
상기 헤테로이관능성 단분산 폴리에틸렌 글리콜을 합성하는 전형적인 예로서는, 이하의 공정을 들 수 있다. 여기에서는, 관능기로서 아지드기 및 p-니트로페닐 카보네이트기를 도입한 화합물에 대하여 예시한다.Typical examples of synthesizing the heterobifunctional monodisperse polyethylene glycol include the following steps. Here, as a functional group, the compound which introduce|transduced the azide group and p-nitrophenyl carbonate group is illustrated.
(식 (16) 중, P8은 카르복시기의 보호기이고, P9는 히드록시기의 보호기이다.)(In formula (16), P 8 is a protecting group of a carboxy group, and P 9 is a protecting group of a hydroxyl group.)
상기 식 (16)에서 나타내어지는 화합물을 무수 용매 중, 강염기 존재 하에서 모노메틸 단분산 폴리에틸렌 글리콜의 알킬 또는 아릴 술폰산 에스테르, 또는 모노메틸 단분산 폴리에틸렌 글리콜의 할로겐화물에 대해서 친핵성 치환 반응을 겪게하고, 하기 식 (17)에서 나타내어지는 화합물을 얻는다.subjecting the compound represented by the formula (16) to a nucleophilic substitution reaction for an alkyl or aryl sulfonic acid ester of monomethyl monodisperse polyethylene glycol or a halide of monomethyl monodisperse polyethylene glycol in an anhydrous solvent in the presence of a strong base; A compound represented by the following formula (17) is obtained.
상기 식 (17)에서 나타내어지는 화합물의 보호기 P8을 탈보호한 후, 축합제의 존재 하에서, 얻어진 화합물을 3-아지드프로필아민과 반응시키고, 하기 식 (18)에서 나타내어지는 화합물을 얻는다.After deprotecting the protecting group P 8 of the compound represented by the formula (17), the obtained compound is reacted with 3-azidepropylamine in the presence of a condensing agent to obtain a compound represented by the following formula (18).
상기 식 (18)에서 나타내어지는 화합물의 보호기 P9을 탈보호한 후, 염기의 존재 하에서, 얻어진 화합물을 p-니트로페닐 클로로포르메이트와 반응시키고, 하기 식 (19)에서 나타내어지는 화합물을 얻는다.After deprotecting the protecting group P 9 of the compound represented by the formula (18), the obtained compound is reacted with p-nitrophenyl chloroformate in the presence of a base to obtain a compound represented by the following formula (19).
(E) 본 발명의 더욱 바람직한 다른 실시 형태에 있어서는, 식 (1)의 A1은 -C(O)NH-(CH2)m1- 또는 -C(O)NH-(CH2)m1-L2-(CH2)m2-를 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합이고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수이며, B1은 -C(O)NH-(CH2)m3- 또는 -C(O)NH-(CH2)m3-L4-(CH2)m4-를 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합이고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수이다. 더욱 바람직하게는, A1은 -C(O)NH-(CH2)m1-를 나타내고, m1은 1 내지 5의 정수이고, B1은 -C(O)NH-(CH2)m3-NHC(O)-(CH2)m4-를 나타내고 m3 및 m4는 각각 독립적으로 1 내지 5의 정수이다.(E) In another preferred embodiment of the present invention, A 1 in formula (1) is -C(O)NH-(CH 2 ) m1- or -C(O)NH-(CH 2 ) m1 -L 2 -(CH 2 ) m2 - is represented, L 2 is an ether bond, an amide bond or a urethane bond, m1 and m2 are each independently an integer of 1 to 5, B 1 is -C(O)NH-(CH 2 ) represents m3 - or -C(O)NH-(CH 2 ) m3 -L 4 -(CH 2 ) m4 -, L 4 is an ether bond, an amide bond or a urethane bond, and m3 and m4 are each independently It is an integer from 1 to 5. More preferably, A 1 represents -C(O)NH-(CH 2 ) m1 -, m1 is an integer from 1 to 5, and B 1 is -C(O)NH-(CH 2 ) m3 -NHC (O)-(CH 2 ) m4 -, and m3 and m4 are each independently an integer of 1 to 5.
상기 헤테로이관능성 단분산 폴리에틸렌 글리콜을 합성하는 전형적인 예로서는, 이하의 공정을 들 수 있다. 여기에서는, 관능기로서 디벤조시클로옥틴 (DBCO)기 및 말레이미드기를 도입한 화합물에 대하여 예시한다.Typical examples of synthesizing the heterobifunctional monodisperse polyethylene glycol include the following steps. Here, as a functional group, the compound which introduce|transduced the dibenzocyclooctyne (DBCO) group and the maleimide group is exemplified.
(식 (20) 중, P10은 카르복시기의 보호기이고, P11은 아미노기의 보호기이다.)(In formula (20), P 10 is a protecting group of a carboxy group, and P 11 is a protecting group of an amino group.)
상기 식 (20)에서 나타내어지는 화합물을 무수 용매 중, 강염기 존재 하에서 모노메틸 단분산 폴리에틸렌 글리콜의 알킬 또는 아릴 술폰산 에스테르, 또는 모노메틸 단분산 폴리에틸렌 글리콜의 할로겐화물에 대해서 친핵성 치환 반응을 겪게하고, 하기 식 (21)에서 나타내어지는 화합물을 얻는다.subjecting the compound represented by the formula (20) to a nucleophilic substitution reaction for an alkyl or aryl sulfonic acid ester of monomethyl monodisperse polyethylene glycol or a halide of monomethyl monodisperse polyethylene glycol in an anhydrous solvent in the presence of a strong base; A compound represented by the following formula (21) is obtained.
상기 식 (21)에서 나타내어지는 화합물의 보호기 P10을 탈보호한 후, 축합제의 존재 하에서, 얻어진 화합물을 디벤조시클로옥틴 (DBCO)-아민 유도체와 반응시키고, 하기 식 (22)에서 나타내어지는 화합물을 얻는다.After deprotecting the protecting group P 10 of the compound represented by the formula (21), in the presence of a condensing agent, the obtained compound is reacted with a dibenzocyclooctyne (DBCO)-amine derivative, and the compound represented by the following formula (22) is get the compound.
상기 식 (22)에서 나타내어지는 화합물의 보호기 P11을 탈보호한 후, 얻어진 화합물을 N-숙신이미딜 3-말레이미도프로피온산과 반응시키고, 하기 식 (23)에서 나타내어지는 화합물을 얻는다.After deprotecting the protecting group P 11 of the compound represented by the formula (22), the obtained compound is reacted with N-succinimidyl 3-maleimidopropionic acid to obtain a compound represented by the following formula (23).
본 발명의 다른 측면에서는, 식 (2)로 표시되는, 헤테로이관능성 단분산 폴리에틸렌 글리콜을 포함하는 항체-약물 복합체가 제공된다.In another aspect of the present invention, an antibody-drug complex comprising a heterobifunctional monodisperse polyethylene glycol represented by Formula (2) is provided.
본 발명의 식 (2)에 있어서의 R1은 탄화수소기 또는 수소 원자이다. 탄화수소기의 탄소수는 7 이하인 것이 바람직하다. 구체적인 탄화수소기의 예로서는 메틸기, 에틸기, 프로필기, 이소프로필기, 3차-부틸기, 페닐기 및 벤질기 등을 들 수 있다. R1의 바람직한 실시 형태로서는 메틸기 또는 수소 원자이며, 더욱 바람직하게는 메틸기이다.R< 1 > in Formula (2) of this invention is a hydrocarbon group or a hydrogen atom. It is preferable that carbon number of a hydrocarbon group is 7 or less. Specific examples of the hydrocarbon group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, a phenyl group, and a benzyl group. As a preferable embodiment of R< 1 >, it is a methyl group or a hydrogen atom, More preferably, it is a methyl group.
본 발명의 식 (2)에 있어서의 n는, 단분산 폴리에틸렌 글리콜의 반복 단위수를 나타내고, 3 내지 72의 정수이며, 바람직하게는 4 내지 48의 정수이며, 더욱 바람직하게는 6 내지 36의 정수이며, 특히 바람직하게는 8 내지 24의 정수이다.n in the formula (2) of the present invention represents the number of repeating units of monodisperse polyethylene glycol, and is an integer of 3-72, preferably an integer of 4-48, more preferably an integer of 6-36 and particularly preferably an integer of 8 to 24.
본 명세서에 있어서, 식 (2) 중의 X2 및 Y2 중 하나는 항체이며, 다른 하나는 약물이다.In the present specification, one of X 2 and Y 2 in Formula (2) is an antibody, and the other is a drug.
본 명세서에서 사용하는 용어 "항체"란, 그의 가장 광의의 의미로 사용되며 구체적으로는, 모노클로날 항체, 폴리클로날 항체, 다이머, 멀티머, 다중특이성 항체 (예를 들면, 이중특이성 항체) 및 항체 단편을, 그것들이 바람직한 생물학적 활성을 나타내는 한, 포함한다(Miller, K. et al. J. Immunol. 2003, 170, 4854-4861).As used herein, the term "antibody" is used in its broadest sense and specifically, monoclonal antibody, polyclonal antibody, dimer, multimer, multispecific antibody (eg, bispecific antibody) and antibody fragments, so long as they exhibit the desired biological activity (Miller, K. et al. J. Immunol. 2003, 170, 4854-4861).
항체는, 마우스 항체, 인간 항체, 인간화 항체 또는 키메라 항체, 또는 다른 종들 유래일 수 있다. 항체는, 특정의 항원을 인식하고 결합하는 것이 가능한, 면역계에 의해서 생성되는 단백질이다(Janeway, C.; Travers, P.; Walport, M.; Shlomchik, M. Immunobiology, 5th ed.; Garland Publishing: New York, 2001).The antibody may be from a mouse antibody, a human antibody, a humanized antibody or a chimeric antibody, or from other species. Antibodies are proteins produced by the immune system that are capable of recognizing and binding to specific antigens (Janeway, C.; Travers, P.; Walport, M.; Shlomchik, M. Immunobiology, 5th ed.; Garland Publishing: New York, 2001).
표적 항원은, 일반적으로는, 복수의 항체들 상에 있는 CDR에 의해 인식되는 다수의 결합 부위(에피토프라고도 불린다)를 가진다. 다른 에피토프에 특이적으로 결합하는 항체는, 다른 구조를 가진다. 따라서, 어느 하나의 항원은, 하나 보다 많은 대응하는 항체를 가질 수 있다. 항체는, 전장 면역글로불린 분자(full-length immunoglobulin molecule), 또는 전장 면역글로불린 분자의 면역학적 활성 부분(즉, 대상으로 하는 항원 또는 그 부분에 면역특이적으로 결합하는 항원 결합 부위를 포함한 분자)을 포함한다. 그러한 표적으로서는, 암 세포 및 자가면역질환에 관련하는 자가면역 항체를 생성하는 세포를 들 수 있지만, 이것들에 한정되지 않는다. 본 명세서에 있어서 개시되는 면역글로불린은, 임의의 타입(예를 들면, IgG, IgE, IgM, IgD 또는 IgA), 클래스 (예를 들면, IgG1, IgG2, IgG3, IgG4, IgA1 또는 IgA2) 또는 이들의 서브클래스(subclass)일 수 있다. 상기 면역글로불린은, 임의의 종들에서 유래할 수 있다. 그러나, 한 실시 형태에 있어서, 상기 면역글로불린은, 인간 기원, 마우스 기원, 또는 토끼 기원이다.A target antigen, generally, has multiple binding sites (also called epitopes) recognized by CDRs on multiple antibodies. Antibodies that specifically bind to different epitopes have different structures. Thus, any one antigen may have more than one corresponding antibody. An antibody is a full-length immunoglobulin molecule, or an immunologically active portion of a full-length immunoglobulin molecule (ie, a molecule comprising an antigen of interest or an antigen-binding site that immunospecifically binds to that portion). include Examples of such targets include, but are not limited to, cancer cells and cells that produce autoimmune antibodies related to autoimmune diseases. The immunoglobulins disclosed herein may be of any type (eg, IgG, IgE, IgM, IgD or IgA), class (eg, IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2), or their It may be a subclass. The immunoglobulin may be from any species. However, in one embodiment, the immunoglobulin is of human origin, mouse origin, or rabbit origin.
폴리클로날 항체는, 예를 들어 면역화된 동물의 혈청으로부터 유래된 것 등의, 항체 분자의 불균일 집단이다. 당업계에 공지된 다양한 절차를 이용하여 대상 항원에 대한 폴리클로날 항체를 제조할 수 있다. 예를 들면, 폴리클로날 항체를 제조하기 위해서, 대상 항원 또는 그의 유도체를 주사하고, 토끼, 마우스, 래트 및 기니피그를 포함하지만 그것들로 한정되지 않는 다양한 숙주 동물을 면역화시킬 수 있다. 숙주 종에 따라, 프로인드(완전 및 불완전) 어쥬번트(Freund's (complete and incomplete) adjuvant), 수산화 알루미늄 등의 미네랄 겔, 리소레시틴 등의 표면 활성 물질, 플루로닉 폴리올(pluronic polyol), 폴리음이온(polyanion), 펩티드, 오일 에멀젼(oil emulsion), 키홀-림펫 헤모사이아닌(keyhole limpet hemocyanin), 디니트로페놀, 및 BCG (Bacille Calmett-Guerin) 및 코리네박테리움 파붐(Corynebacterium parvum) 등의 잠재적으로 유용한 인간 어쥬번트를 포함하지만 그것들로 한정되지 않는, 다양한 어쥬번트를 이용하여 면역 응답을 증가시킬 수 있다. 이러한 어쥬번트는 당업계에서도 공지되어있다.Polyclonal antibodies are heterogeneous populations of antibody molecules, such as those derived from, for example, the serum of an immunized animal. A variety of procedures known in the art can be used to prepare polyclonal antibodies to an antigen of interest. For example, to prepare polyclonal antibodies, the antigen of interest or a derivative thereof may be injected and a variety of host animals, including but not limited to rabbits, mice, rats, and guinea pigs, may be immunized. Depending on the host species, Freund's (complete and incomplete) adjuvant, mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions (polyanion), peptide, oil emulsion, keyhole-limpet hemocyanin, dinitrophenol, and potential of Bacille Calmett-Guerin (BCG) and Corynebacterium parvum, etc. A variety of adjuvants can be used to increase the immune response, including, but not limited to, human adjuvants useful as human adjuvants. Such adjuvants are also known in the art.
모노클로날 항체는, 특정의 항원 결정기(예를 들면, 세포 항원(암 또는 자가면역 세포 항원), 바이러스 항원, 미생물 항원, 단백질, 펩티드, 탄수화물, 화학물질, 핵산 또는 이들의 항원-결합 단편)에 대한 항체의 균일한 집단이다. 당업계에 공지된 임의의 기법을 이용하여 대상 항원에 대한 모노크로날 항체(mAb)를 제조할 수 있다. 이것들은, 『Kohler, G; Milstein, C. Nature 1975, 256, 495-497』가 최초로 기재한 하이브리도마 기법(hybridoma technique), 인간 B 세포 하이브리도마 기법 (Kozbor, D. et al. Immunol. Today 1983, 4, 72-79) 및 EBV-하이브리도마 기법(Cole, S. P. C. et al. Monoclonal Antibodies and Cancer Therapy; Alan R. Liss: New York, 1985, pp. 77-96)을 포함하지만, 이들로 한정되지 않는다. 이러한 항체는, IgG, IgM, IgE, IgA 및 IgD를 포함하는 임의의 면역글로불린의 클래스 및 그들의 임의의 서브클래스일 수 있다. 본 발명에 있어서 모노클로날 항체를 생산하는 하이브리도마는, 인 비트로(in vitro) 또는 인 비보(in vivo)로 배양할 수 있다.Monoclonal antibodies may contain specific antigenic determinants (eg, cellular antigens (cancer or autoimmune cell antigens), viral antigens, microbial antigens, proteins, peptides, carbohydrates, chemicals, nucleic acids, or antigen-binding fragments thereof). is a homogeneous population of antibodies to Monoclonal antibodies (mAbs) to the antigen of interest can be prepared using any technique known in the art. These are, Kohler, G; Milstein, C. Nature 1975, 256, 495-497] first described hybridoma technique, human B cell hybridoma technique (Kozbor, D. et al. Immunol. Today 1983, 4, 72- 79) and the EBV-hybridoma technique (Cole, S. P. C. et al. Monoclonal Antibodies and Cancer Therapy; Alan R. Liss: New York, 1985, pp. 77-96). Such antibodies may be of any class and any subclass of immunoglobulins, including IgG, IgM, IgE, IgA and IgD. In the present invention, the hybridoma producing the monoclonal antibody can be cultured in vitro or in vivo.
모노클로날 항체는, 인간 모노클로날 항체, 인간화 모노클로날 항체, 키메라 모노클로날 항체 및 항체 단편을 포함하지만 그것들로 한정되지 않는다. 인간 모노클로날 항체는, 당업계에 공지된 다수의 기법 중 임의의 것(예를 들면, Teng, N. N. et al. Proc. Natl. Acad. Sci. USA. 1983, 80, 7308-7312, Kozbor, D. et al. Immunology Today 1983, 4, 72-79, Olsson L. et al. Meth. Enzymol. 1982, 92, 3-16, 및 U.S. 특허 제5,939,598호 및 제5,770,429호를 참조)에 의해 제조될 수 있다. 키메라 모노클로날 항체 또는 인간화 모노클로날 항체 등의 재조합(recombinant) 항체는, 당업계에 공지된 표준 재조합 DNA 기법을 이용하여 제조할 수 있다(예를 들면, U.S. 특허 제4,816,567호 및 제4,816,397호 참조).Monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, chimeric monoclonal antibodies, and antibody fragments. Human monoclonal antibodies can be prepared using any of a number of techniques known in the art (eg, Teng, N. N. et al. Proc. Natl. Acad. Sci. USA. 1983, 80, 7308-7312, Kozbor, D. et al. Immunology Today 1983, 4, 72-79, Olsson L. et al. Meth. Enzymol. 1982, 92, 3-16, and U.S. Patent Nos. 5,939,598 and 5,770,429) can Recombinant antibodies, such as chimeric monoclonal antibodies or humanized monoclonal antibodies, can be prepared using standard recombinant DNA techniques known in the art (e.g., U.S. Patent Nos. 4,816,567 and 4,816,397) Reference).
항체의 표면 재구성(resurfacing) 처리에 의해서, 항체의 면역원성을 또한 감소시킬 수 있다(U.S. 특허 제5,225,539호 및 유럽 특허 제0239400호, 제0519596호 및 제0592106호를 참조).The immunogenicity of the antibody can also be reduced by surface resurfacing treatment of the antibody (see U.S. Patent Nos. 5,225,539 and EP 0239400, 0519596 and 0592106).
본 발명의 일 실시 형태에 있어서, 항체는 이중특이성 항체일 수 있다. 이중 특이성 항체를 제조하기 위한 방법은, 당업계에서 공지되어있다. 종래의 전장 이중특이성 항체의 제조 방법은, 2개의 사슬이 다른 특이성을 갖는 2개의 면역글로불린 중쇄-경쇄 쌍의 동시 발현을 이용한다(Milstein, C. et al. Nature 1983, 305, 537-539 참조). 또한, 다른 방법에 따라서 원하는 결합 특이성(항체-항원 결합 부위)을 가지는 항체 가변 도메인을 면역글로불린 불변 도메인 서열과 융합시키는 것으로써, 이중특이성 항체를 제조할 수 있다.In one embodiment of the present invention, the antibody may be a bispecific antibody. Methods for making bispecific antibodies are known in the art. Conventional methods for preparing full-length bispecific antibodies utilize the co-expression of two immunoglobulin heavy chain-light chain pairs in which the two chains have different specificities (see Milstein, C. et al. Nature 1983, 305, 537-539). . In addition, a bispecific antibody can be prepared by fusing an antibody variable domain having a desired binding specificity (antibody-antigen binding site) with an immunoglobulin constant domain sequence according to another method.
그 외의 유용한 항체는, F(ab') 2 단편, Fab'단편, Fab 단편, Fvs, 단쇄 항체 (SCA) (예를 들면, U.S. 특허 제4,946,778호, Bird, R. E. et al. Science 1988, 242, 423-442, Huston, J. S. et al. Proc. Natl. Acad. Sot USA 1988, 85, 5879-5883, 및 Ward, E. S. et al. Nature 1989, 334, 544-554에 기재되어 있음), scFv, sc-Fv-Fc, FvdsFv, 미니바디(minibody), 디아바디(diabody), 트리아바디(triabody), 테트라바디(tetrabody), 및 CDR을 포함하는 항체와 같은 동일한 특이성을 가지는 임의의 다른 분자, 예를 들면 도메인 항체 등을 들 수 있지만, 이것들로 한정되지 않는 항체의 단편을 포함한다.Other useful antibodies include, but are not limited to, F(ab′) 2 fragments, Fab′ fragments, Fab fragments, Fvs, single chain antibodies (SCA) (eg, U.S. Patent Nos. 4,946,778, Bird, R. E. et al. Science 1988, 242, 423-442, Huston, J. S. et al. Proc. Natl. Acad. Sot USA 1988, 85, 5879-5883, and Ward, E. S. et al. Nature 1989, 334, 544-554), scFv, sc -Fv-Fc, FvdsFv, minibody, diabody, triabody, tetrabody, and any other molecule having the same specificity, such as an antibody comprising a CDR Examples thereof include, but are not limited to, domain antibodies, and antibody fragments.
본 발명의 바람직한 실시 형태에서는, 암의 치료 또는 예방을 위한 공지된 항체를 이용할 수 있다. 발현이 암, 세포 증식 장애 또는 종양의 세포 상에서 발현과 상관관계에 있는 임의의 표적 단백질을 포함하는, 모든 표적 단백질들을, 항체의 표적으로 할 수 있다.In a preferred embodiment of the present invention, known antibodies for the treatment or prevention of cancer can be used. Any target protein, including any target protein whose expression correlates with expression on cells of a cancer, cell proliferative disorder, or tumor, can be targeted by an antibody.
본 발명의 바람직한 실시 형태에 있어서, 항체는 암의 치료에 유용하다. 암의 치료에 이용 가능한 항체의 예는, 비호지킨 림프종을 가지는 환자의 치료를 위한 키메라 항-CD20 모노클로날 항체인 RITUXAN (등록 상표) (Genentech Inc.), 난소 암의 치료를 위한 마우스 항체인 OVAREX (AltaRex Corp.), 결직장(colorectal) 암의 치료를 위한 마우스 IgG2a 항체인 PANOREX (Glaxo Wellcome Inc.), 두부암(head cancer) 또는 경부암(neck cancer) 등의 표피세포 성장 인자 양성 암의 치료를 위한 항-EGFR IgG 키메라 항체인 CETUXIMAB ERBITUX (ImClone Systems Inc.), 육종의 치료를 위한 인간화 항체인 VITAXIN (MedImmune Inc.), 만성 림프구 백혈병(CLL)의 치료를 위한 인간화 IgG1 항체인 CAMPATH I/H (Leukosite Inc.), 급성 골수성 백혈병(AML)의 치료를 위한 인간화 항-CD33 IgG 항체인 Smart M195 (Protein Design Labs Inc.), 비호지킨 림프종의 치료를 위한 인간화 항-CD22 IgG 항체인 LYMPHOCIDE (Immunomedics Inc.), 비호지킨 림프종의 치료를 위한 인간화 항-HLA-DR 항체인 Smart ID10 (Protein Design Labs Inc.), 비호지킨 림프종의 치료를 위한 방사성 원소 표지화 마우스 항-HLA-Dr10 항체인 Oncolym (Techniclone Inc.), 호지킨병(Hodgkin's disease) 또는 비호지킨 림프종의 치료를 위한 인간화 항-CD2 mAb인 ALLOMUNE (BioTransplant Inc.), 폐암 및 결직장 암의 치료를 위한 항-VEGF 인간화 항체인 AVASTIN (Genentech Inc.), 비호지킨 림프종의 치료를 위한 항-CD22 항체인 Epratuzamab (Immunomedics Inc. 및 Amgen Inc.), 및 결직장 암의 치료를 위한 인간화 항-CEA 항체인 CEAcide (Immunomedics Inc.)를 포함하지만, 그것들로 한정되지는 않는다.In a preferred embodiment of the present invention, the antibody is useful for the treatment of cancer. Examples of antibodies available for the treatment of cancer include RITUXAN (registered trademark) (Genentech Inc.), a chimeric anti-CD20 monoclonal antibody for the treatment of patients with non-Hodgkin's lymphoma, a mouse antibody for the treatment of ovarian cancer. OVAREX (AltaRex Corp.), PANOREX (Glaxo Wellcome Inc.), a mouse IgG2a antibody for the treatment of colorectal cancer, epidermal growth factor-positive cancers such as head or neck cancer CETUXIMAB ERBITUX (ImClone Systems Inc.), an anti-EGFR IgG chimeric antibody for treatment, VITAXIN (MedImmune Inc.), a humanized antibody for the treatment of sarcoma, CAMPATH I, a humanized IgG1 antibody, for the treatment of chronic lymphocytic leukemia (CLL) /H (Leukosite Inc.), Smart M195 (Protein Design Labs Inc.), a humanized anti-CD33 IgG antibody for the treatment of acute myeloid leukemia (AML), LYMPHOCIDE, a humanized anti-CD22 IgG antibody for the treatment of non-Hodgkin's lymphoma (Immunomedics Inc.), Smart ID10 (Protein Design Labs Inc.), a humanized anti-HLA-DR antibody for the treatment of non-Hodgkin's lymphoma, Oncolym, a radio-element labeled mouse anti-HLA-Dr10 antibody for the treatment of non-Hodgkin's lymphoma (Techniclone Inc.), ALLOMUNE (BioTransplant Inc.), a humanized anti-CD2 mAb for the treatment of Hodgkin's disease or non-Hodgkin's lymphoma, AVASTIN, an anti-VEGF humanized antibody for the treatment of lung and colorectal cancer (Genentech Inc.), Epratuzamab (Immunomedics Inc. and Amgen Inc.), an anti-CD22 antibody for the treatment of non-Hodgkin's lymphoma, and a humanized anti-C for the treatment of colorectal cancer The EA antibody, CEAcide (Immunomedics Inc.), is included, but is not limited thereto.
본 발명의 바람직한 실시 형태에 있어서, 항체는 이하의 항원에 대한 항체이다: CA125, CA15-3, CA19-9, L6, 루이스(Lewis) Y, 루이스 X, 알파페토프로테인(alpha fetoprotein), CA242, 태반성 알칼리포스파타제(placental alkaline phosphatase), 전립선 특이성 막항원, EphB2, TMEFF2, 전립선 산성 포스파타아제(prostatic acid phosphatase), 표피 증식 인자, MAGE-1, MAGE-2, MAGE-3, MAGE-4, 항-트랜스페린 수용체, p97, MUC1-KLH, CEA, gp 100, MART 1, 전립선 특이성 항원, IL-2 수용체, CD20, CD52, CD33, CD22, 인간 융모성 고나도트로핀(human chorionic gonadotropin), CD38, CD40, 뮤신(mucin), P21, MPG 및 Neu 암유전자 산물.In a preferred embodiment of the present invention, the antibody is an antibody against the following antigens: CA125, CA15-3, CA19-9, L6, Lewis Y, Lewis X, alpha fetoprotein, CA242, placental alkaline phosphatase, prostate-specific membrane antigen, EphB2, TMEFF2, prostatic acid phosphatase, epidermal growth factor, MAGE-1, MAGE-2, MAGE-3, MAGE-4, anti-transferrin receptor, p97, MUC1-KLH, CEA, gp 100,
몇몇의 특이적인 유용한 항체는, 예를 들면, BR96 mAb (Trail, P. A. et al. Science 1993, 261, 212-215), BR64 (Trail, P. A. et al. Cancer Research 1997, 57, 100-105) 또는 S2C6 mAb (Francisco, J. A. et al. Cancer Res. 2000, 60, 3225-3231)등의 CD40 항원에 대한 mAb, 또는 U.S. 특허 출원 공개 번호 제2003/0211100호 및 제2002/0142358호에 개시되고 있는 그 외의 항-CD40 항체, 예를 들면, 1F6 mAb 및 2F2 mAb 등의 CD70 항원에 대한 mAb, 및 예를 들면, AC10 (Bowen, M. A. et al. J. Immunol. 1993, 151, 5896-5906, Wahl, A. F. et al. Cancer Res. 2002, 62(13), 3736-3742) 또는 MDX-0060 (U.S. 특허 출원 공개 번호 제2004/0006215호) 등의 CD30 항원에 대한 mAb를 포함하지만, 그것들로 한정되지는 않는다.Some specific useful antibodies are, for example, BR96 mAb (Trail, P. A. et al. Science 1993, 261, 212-215), BR64 (Trail, P. A. et al. Cancer Research 1997, 57, 100-105) or A mAb against the CD40 antigen, such as the S2C6 mAb (Francisco, J. A. et al. Cancer Res. 2000, 60, 3225-3231), or U.S. Other anti-CD40 antibodies disclosed in Patent Application Publication Nos. 2003/0211100 and 2002/0142358, e.g., mAbs against the CD70 antigen, such as 1F6 mAb and 2F2 mAb, and e.g., AC10 ( Bowen, M. A. et al. J. Immunol. 1993, 151, 5896-5906, Wahl, A. F. et al. Cancer Res. 2002, 62(13), 3736-3742) or MDX-0060 (U.S. Patent Application Publication No. 2004). /0006215), and the like).
본 발명에서 이용할 수 있는 약물에는, 화학요법제가 포함된다. 화학요법제는, 암의 치료에 있어서 유용한 화합물이다. 화학요법제의 예로서는 다음의 것이 포함된다: 알킬화제, 예를 들면 티오테파(thiotepa) 또는 시클로포스파미드 (CYTOXAN (상표)); 알킬 술포네이트류, 예를 들면, 부설판(busulfan), 임프로설판(improsulfan) 또는 피포술판(piposulfan); 아지리딘류(aziridines) 예를 들면, 벤조포다(benzodopa), 카르보콘(carboquone), 메투르포다(meturedopa) 또는 우레포다(uredopa); 알트레타민(altretamine), 트리에틸렌멜라민(triethylenemelamine), 트리에틸렌포스포아미드(triethylenethiophosphoramide), 트리에틸렌티오포스포아미드(triethylenephosphoramide) 및 트리메틸로멜라민(trimethylolomelamine)을 포함하는 메틸멜라민류(methylamelamines) 및 에틸렌이민류(ethyleneimines); 아세토게닌류(acetogenins) (특히 부라타신(bullatacin) 및 부라타시논(bullatacinone)); 캠토테신(camptothecin) (합성 유사체인 토포테칸 포함); 브리오스타틴(bryostatin); 칼리스타틴(callystatin); CC-1065 (이것의 아도제레신(adozelesin), 카르제레신(carzelesin) 및 비제레신(bizelesin) 합성 유사체 포함); 크립토파이신류(cryptophycins) (특히 크립토파이신 1 및 크립토파이신 8); 돌라스태틴(dolastatin); 듀오카르마이신(duocarmycin) (합성 유사체인 KW-2189 및 CBI-TMI 포함); 엘류테로빈(eleutherobin); 판크라티스타틴(pancratistatin); 살코딕틴(sarcodictyin); 스폰기스타틴(spongistatin); 니트로겐 머스타드류(nitrogen mustards), 예를 들면, 클로람부실(chlorambucil), 클로나파진(chlornaphazine), 클로포스파미드(cholophosphamide), 에스트라머스틴(estramustine), 이포스파마이드(ifosfamide), 메클로레타민(mechlorethamine), 메클로레타민 옥사이드 하이드로클로라이드(mechlorethamine oxide hydrochloride), 멜파란(melphalan), 노벰비킨(novembichin), 페네스테린(phenesterine), 프레드니머스틴(prednimustine), 트로포스파미드(trofosfamide) 또는 우라실 머스타드(uracil mustard); 니트로스우레아류(nitrosoureas), 예를 들면, 카무스틴(carmustine), 클로로조토신(chlorozotocin), 포트머스틴(fotemustine), 로머스틴(lomustine), 니머스틴(nimustine) 또는 라니머스틴(ranimustine); 항생제, 예를 들면, 엔다이인 항생제(enediyne antibiotics) (예를 들면, 칼리키아마이신(calicheamicin), 특히 칼리키아마이신-감마 1 및 칼리키아마이신 세타 I; 예를 들면, Angew Chem Intl. Ed. Engl. 33:183-186 (1994) 참조; 다인마이신(dynemicin) (다인마이신 A를 포함); 에스페라마이신(esperamicin); 또는 네오카르지노스타틴 발색단(neocarzinostatin chromophore) 및 연관된 색소단백질 엔다인 항생제 발색단(related chromoprotein enediyne antibiotic chromophores), 아크라시노마이신(aclacinomysins), 악티노마이신(actinomycin), 아우트라마이신(authramycin), 아자세린(azaserine), 블레오마이신(bleomycins), 칵티노마이신(cactinomycin), 카라비신(carabicin), 카미노마이신(carminomycin), 카르지노필린(carzinophilin); 크로모마이신(chromomycins), 닥티노마이신(dactinomycin), 다우노루비신(daunorubicin), 데토루비신(detorubicin), 6-디아조-5-옥소-L-노르루신, 독소루비신(doxorubicin) (모르폴리노-독소루비신, 시아노모르폴리노-독소루비신, 2-피롤리노-독소루비신 및 데옥시독소루비신 포함), 에피루비신(epirubicin), 에소루비신(esorubicin), 이다루비신(idarubicin), 마르셀로마이신(marcellomycin), 니토마이신(nitomycins), 마이코페놀산(mycophenolic acid), 노갈라마이신(nogalamycin), 올리보마이신(olivomycins), 페프로마이신(peplomycin), 포트피로마이신(potfiromycin), 퓨로마이신(puromycin), 큐라마이신(quelamycin), 로도루비신(rodorubicin), 스트렙토니그린(streptonigrin), 스트렙토조신(streptozocin), 튜베르시딘(tubercidin), 우베니멕스(ubenimex), 지노스타틴(zinostatin), 조루비신(zorubicin); 항-대사제류(anti-metabolites), 예를 들면, 메토트렉세이트(methotrexate) 또는 5-플루오로우라실 (5-FU); 엽산 유사체, 예를 들면, 데모프테린(demopterin), 메토트렉세이트, 프테로프테린(pteropterin) 또는 트리메트렉세이트(trimetrexate); 퓨린 유사체, 예를 들면, 플루다라빈(fludarabine), 6-머캅토퓨린, 티아미퓨린(thiamiprine) 또는 티오구아닌(thioguanine); 피리미딘 유사체, 예를 들면, 안시타빈(ancitabine), 아자시티딘(azacitidine), 6-아자유리딘(6-azauridine), 카르모푸르(carmofur), 시타라빈(cytarabine), 디데옥시유리딘(dideoxyuridine), 독시플루리딘(doxifluridine), 에노시타빈(enocitabine), 플록수리딘(floxuridine) 또는 5-FU; 안드로겐류, 예를 들면, 칼루스테론(calusterone), 드로모스타노론 프로피온산(dromostanolone propionate), 에피티오스타놀(epitiostanol), 메피티오스탄(mepitiostane) 또는 테스토락톤(testolactone); 항-아드레날류(anti-adrenals), 예를 들면, 아미노글루트티미드(aminoglutethimide), 미토탄(mitotane) 또는 트릴로스탄(trilostane); 엽산 보충제(folic acid replenisher), 예를 들면, 프로리닉산(frolinic acid); 아세글라톤(aceglatone); 알도포스파미드 글리코시드(aldophosphamide glycoside); 아미노레불린산(aminolevulinic acid); 암사크린(amsacrine); 베스트라부실(bestrabucil); 비산트렌(bisantrene); 에다트렉세이트(edatraxate); 데포파민(defofamine); 데메콜친(demecolcine); 디아지큐온(diaziquone); 엘포미틴(elfomithine); 엘립티늄 아세테이트(elliptinium acetate); 에포틸론(epothilone); 에토글루시드(etogiucid); 갈륨 질산염(gallium nitrate); 히드록시유레아(hydroxy urea); 렌티난(lentinan); 로니다민(lonidamine); 메이탄시노이드, 예를 들면, 메이탄신(maytansine) 또는 안사미토신(ansamitocins); 미토구아존(mitoguazone); 마이토잔트론(mitoxantrone); 모피다몰(mopidamol); 니트라크린(nitracrine); 펜토스타틴(pentostatin); 페나메트(phenamet); 피라루비신(pirarubicin); 포도필린산(podophyllinic acid); 2-에틸하드라자이드(2-ethylhydrazide); 프로카르바진(procarbazine); PSK (등록 상표); 라조산(razoxane); 리족신(rhizoxin); 시조피란(sizofiran); 스피로게르마늄(spirogermanium); 테누아존산(tenuazonic acid); 트리아지큐온(triaziquone); 2,2',2"-트리클로로트리에틸아민; 트리코테센(trichothecenes) (특히 T-2 톡신, 베라쿠린 A(verracurin A), 로리딘 A(roridin A) 및 안구이딘(anguidine)); 우레탄; 빈데신(vindesine); 다카바진(dacarbazine); 만노머스틴(mannomustine); 미토브로니톨(mitobronitol); 미토락톨(mitolactol); 피포브로만(pipobroman); 가시토신(gacytosine); 아라비노시드(arabinoside) ("Ara-C"); 시클로포스파미드(cyclophosphamide); 티오테파; 탁소이드(taxoids), 예를 들면, 파클리탁셀(paclitaxel) (TAXOL (등록 상표), Bristol-Myers Squibb Oncology) 또는 독세탁셀(doxetaxel) (TAXOTERE (등록 상표), Rhone-Poulenc Rorer); 클로람부실; 젬시타빈(gemcitabine); 6-티오구아닌(6-thioguanine); 머캅토퓨린; 메토트렉세이트; 백금 유사체, 예를 들면, 시스플라틴(cisplatin) 또는 카보플라틴(carboplatin); 빈블라스틴(vinblastine); 백금; 에토포시드(etoposide) (VP-16); 이포스파마이드(ifosfamide); 미토마이신 C; 미토잔트론(mitoxantrone); 빈크리스틴(vincristine); 비노렐빈(vinorelbine); 나벨빈(navelbine); 노반트론(novantrone); 테니포시드(teniposide); 다우노마이신(daunomycin); 아미노프테린(aminopterin); 젤로다(xeloda); 이반드로네이트(ibandronate); CPT-11; 토포아이소머라제 저해제 RFS 2000; 디플루오로메틸로미신(DMFO); 레티노산(retinoic acid); 카페시타빈(capecitabine); 및 상기 중 어느 하나의 약물들의 약제학적으로 허용가능한 염, 산 또는 유도체. 종양에 대한 호르몬의 작용을 조절하거나 저해하는 항-호르몬제가 상기의 정의에 또한 포함된다: 그 예로서, 예를 들면, 타목시펜(tamoxifen), 라록시펜(raloxifene), 아로마타제(aromatase) 저해 4(5)-이미다졸, 4-히드록시타목시펜(4-hydroxytamoxifen), 트리옥시펜(trioxifene), 케옥시펜(keoxifene), LY 117018, 오나프리스톤(onapristone) 및 토레미펜(toremifene) (화레스톤: Fareston)을 포함하는 항-에스트로겐제; 및 항-안드로겐제, 예를 들면, 플루타미드(flutamide), 니루타미드(nilutamide), 비카루타미드(bicalutamide), 류프롤리드(leuprolide) 또는 고세레린(goserelin); siRNA, 및 상기 중 어느 하나의 약물들의 약제학적으로 허용가능한 염, 산 또는 유도체. 본 발명과 함께 이용할 수 있는 다른 화학요법제가, 미국 특허 출원 공개 번호 제2008/0171040호 및 제2008/0305044호에 개시되고 있으며, 이들은 모두 본 명세서에 참고문헌으로서 통합된다.The drugs usable in the present invention include chemotherapeutic agents. Chemotherapeutic agents are compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include: alkylating agents such as thiotepa or cyclophosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan or piposulfan; aziridines such as benzodopa, carboquone, meturedopa or uredopa; Methylmelamines and ethylene, including altretamine, triethylenemelamine, triethylenethiophosphoramide, triethylenethiophosphoramide and trimethylolomelamine ethyleneimines; acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; Callistatin (callystatin); CC-1065 (including its synthetic analogues of adozelesin, carzelesin and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs KW-2189 and CBI-TMI); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, Chlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, troposphamide ( trofosfamide) or uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine or ranimustine ; Antibiotics, such as enediyne antibiotics (eg, calicheamicin, in particular calicheamicin-
본 발명의 바람직한 실시 형태에 있어서, 화학요법제는 저분자 약물이다. 저분자 약물은, 바람직하게는 100 내지 1500, 더욱 바람직하게는 120 내지 1200, 더욱 더 바람직하게는 200 내지 1000의 분자량을 갖는다. 전형적으로는, 저분자 약물은 약 1000 미만의 분자량을 가지는 유기, 무기, 또는 유기 금속성 화합물로서 광범위하게 이용된다. 또한, 본 발명의 저분자 약물은, 약 1000 미만의 분자량을 각각 가지는 올리고펩티드류 및 다른 생체 분자들을 또한 포함한다. 저분자 약물은 당업계에서, 예를 들면, 특히 WO 05/058367호, EP-A-85901495호, EP-A-8590319호 및 U.S. 특허 제4,956,303호에서 잘 특징화 되어있고, 이들은 모두 본 명세서에 참고문헌으로서 통합된다.In a preferred embodiment of the present invention, the chemotherapeutic agent is a small molecule drug. The low molecular weight drug preferably has a molecular weight of 100 to 1500, more preferably 120 to 1200, still more preferably 200 to 1000. Typically, low molecular weight drugs are widely used as organic, inorganic, or organometallic compounds having molecular weights less than about 1000. In addition, the low molecular weight drug of the present invention also includes oligopeptides and other biomolecules each having a molecular weight of less than about 1000. Small molecule drugs are known in the art, for example, inter alia in WO 05/058367, EP-A-85901495, EP-A-8590319 and U.S. Pat. It is well characterized in Patent No. 4,956,303, all of which are incorporated herein by reference.
본 발명의 바람직한 저분자 약물은, 항체에 결합이 가능한 저분자 약물이다. 본 발명에는, 공지된 약물 및 공지될 가능성이 있는 약물도 포함한다. 특히 바람직한 저분자 약물에는 세포 독성제가 포함된다.A preferred low-molecular-weight drug of the present invention is a low-molecular-weight drug capable of binding to an antibody. The present invention also includes known drugs and drugs likely to be known. Particularly preferred small molecule drugs include cytotoxic agents.
바람직한 세포 독성제는 메이탄시노이드류(maytansinoids), CC-1065 유사체, 모르폴리노류, 독소루비신류, 탁산류(taxanes), 크립토피신류(cryptophycins), 에포티론류(epothilones), 칼리키아마이신류(calicheamicins), 아우리스타틴류(auristatins), 및 피롤로벤조디아제핀(pyrrolobenzodiazepine) 다이머류를 들 수 있다.Preferred cytotoxic agents include maytansinoids, CC-1065 analogs, morpholinos, doxorubicins, taxanes, cryptophycins, epothilones, calicheamicins (calicheamicins), auristatins, and pyrrolobenzodiazepine dimers.
본 발명의 식 (2)로 표시되는, 헤테로이관능성 단분산 폴리에틸렌 글리콜을 포함하는 항체-약물 복합체는, 식 (1)로 표시되는 헤테로이관능성 단분산 폴리에틸렌 글리콜을 이용하여 항체와 약물을 결합시키는 것으로 제조할 수 있다. 상기 식 (2)로 표시되는 항체-약물 복합체의 제조 방법은, 상기 식 (1)로 표시되는 헤테로이관능성 단분산 폴리에틸렌 글리콜과 약물을 결합시킨 후, 항체를 결합시켜 제조하는 방법 또는 상기 식 (1)로 표시되는 헤테로이관능성 단분산 폴리에틸렌 글리콜과 항체를 결합시킨 후, 약물을 결합시켜 제조하는 방법일 수 있다. 또한, 항체 또는 약물 중 어느 하나를 결합시킨 후에 정제를 실시해도 되거나 또는 항체와 약물의 양자 모두를 결합시킨 후에 정제를 실시해도 된다.The antibody-drug complex comprising the heterobifunctional monodisperse polyethylene glycol represented by the formula (2) of the present invention binds the antibody and the drug using the heterobifunctional monodisperse polyethylene glycol represented by the formula (1) can be manufactured as The method for preparing the antibody-drug complex represented by the formula (2) is a method for preparing by binding the antibody after binding the heterobifunctional monodisperse polyethylene glycol represented by the formula (1) and the drug, or the formula ( After binding the heterobifunctional monodisperse polyethylene glycol represented by 1) and the antibody, it may be a method of manufacturing by binding a drug. Further, purification may be carried out after binding either the antibody or the drug, or purification may be carried out after binding both the antibody and the drug.
상기 식 (1)로 표시되는 헤테로이관능성 단분산 폴리에틸렌 글리콜과 약물을 결합시킨 화합물은, 예를 들면 컬럼 크로마토그래피, 추출, 재결정, 흡착제 처리, 재침전 또는 초임계 추출 등의 정제 수단에 의해 정제할 수 있다. 또한, 상기 식 (1)로 표시되는 헤테로이관능성 단분산 폴리에틸렌 글리콜과 항체를 결합시킨 화합물 및 상기 식 (1)로 표시되는 헤테로이관능성 단분산 폴리에틸렌 글리콜과 항체와 약물의 양자 모두를 결합시킨 항체-약물 복합체는, 예를 들면 컬럼 크로마토그래피, 추출 또는 흡착제 처리 등의 정제 수단에 의해 정제할 수 있다.The compound in which the heterobifunctional monodisperse polyethylene glycol represented by the formula (1) is bound to a drug is purified by purification means such as column chromatography, extraction, recrystallization, adsorbent treatment, reprecipitation or supercritical extraction, for example. can do. In addition, a compound in which the heterobifunctional monodisperse polyethylene glycol represented by the formula (1) and an antibody are bound, and an antibody in which both the heterobifunctional monodisperse polyethylene glycol represented by the formula (1) and both the antibody and the drug are bound. - The drug complex can be purified, for example, by a purification means such as column chromatography, extraction, or treatment with an adsorbent.
본 발명의 식 (1)로 표시되는 헤테로이관능성 단분산 폴리에틸렌 글리콜을 통해 항체에 결합한 약물의 수는, 항체 당 약물의 평균 수에 의해서 정의된다. 바람직한 약물의 수는 1 내지 20개이며, 더욱 바람직하게는 2 내지 16개이며, 더욱 바람직하게는 3 내지 12개이며, 특히 바람직하게는 4 내지 8개이다.The number of drugs bound to the antibody via the heterobifunctional monodisperse polyethylene glycol represented by Formula (1) of the present invention is defined by the average number of drugs per antibody. The preferred number of drugs is 1 to 20, more preferably 2 to 16, still more preferably 3 to 12, and particularly preferably 4 to 8.
ADC에 있어서의 항체 당 약물의 수는, 예를 들면 자외선/가시광선 분광법, 질량분석법, ELISA법, 전기 영동, HPLC, 또는 이것들을 조합한 방법 등인, 당업자에게 공지된 방법에 따라 결정될 수 있다.The number of drugs per antibody in ADC can be determined according to a method known to those skilled in the art, for example, ultraviolet/visible light spectroscopy, mass spectrometry, ELISA method, electrophoresis, HPLC, or a combination thereof.
본 발명의 식 (2)에서의 A2는, 분기 부분의 4급 탄소 원자와 X2와의 사이의 2가의 스페이서이고, 식 (2)에서의 B2은, 분기 부분의 4급 탄소 원자와 Y2와의 사이의 2가의 스페이서이며, 이들은 각각 공유결합으로 구성된다.A 2 in the formula (2) of the present invention is a divalent spacer between the quaternary carbon atom of the branched moiety and X 2 , and B 2 in the formula (2) is a quaternary carbon atom of the branched moiety and Y It is a bivalent spacer between 2 and each of these is constituted by a covalent bond.
구체적으로는, A2은 -L1-(CH2)m1-L5-, -L1-(CH2)m1-L2-(CH2)m2-L5- 또는 단결합을 나타내고, L1은 에테르 결합, 아미드 결합, 우레탄 결합, 2급 아미노기 또는 단결합을 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수를 나타낸다. 여기서, L5는, 상기 식 (1)로 표시되는 헤테로이관능성 단분산 폴리에틸렌 글리콜의 X1에 포함되는 관능기와 항체 또는 약물에 존재하는 관능기와의 반응으로 형성되는 원자단이며, 바람직하게는 아미드 결합, 우레탄 결합, 티오에테르 결합, 디술피드 결합, 카보네이트 결합, 에스테르 결합, 에테르 결합, 1H-1,2,3-트리아졸-1,4-디일 구조, 2급 아미노기, 히드라지드기, 옥시아미드기 또는 이들 중 어느 것을 포함하는 탄화수소기이다.Specifically, A 2 represents -L 1 -(CH 2 ) m1 -L 5 -, -L 1 -(CH 2 ) m1 -L 2 -(CH 2 ) m2 -L 5 - or a single bond, L 1 represents an ether bond, an amide bond, a urethane bond, a secondary amino group or a single bond, L 2 represents an ether bond, an amide bond or a urethane bond, and m1 and m2 each independently represent an integer of 1 to 5. Here, L 5 is an atomic group formed by reaction of a functional group included in X 1 of the heterobifunctional monodisperse polyethylene glycol represented by the formula (1) and a functional group present in an antibody or drug, preferably an amide bond , urethane bond, thioether bond, disulfide bond, carbonate bond, ester bond, ether bond, 1H-1,2,3-triazole-1,4-diyl structure, secondary amino group, hydrazide group, oxyamide group or a hydrocarbon group containing any of these.
또한, B2는 -L3-(CH2)m3-L6-, -L3-(CH2)m3-L4-(CH2)m4-L6- 또는 단결합을 나타내고, L3은 아미드 결합 또는 단결합을 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수를 나타낸다. 여기서 L6은, 상기 식 (1)로 표시되는 헤테로이관능성 단분산 폴리에틸렌 글리콜의 Y1에 포함되는 관능기와 항체 또는 약물에 존재하는 관능기와의 반응으로 형성되는 원자단이며, 바람직하게는 아미드 결합, 우레탄 결합, 티오에테르 결합, 디술피드 결합, 카보네이트 결합, 에스테르 결합, 에테르 결합, 1H-1,2,3-트리아졸-1,4-디일 구조, 2급 아미노기, 히드라지드기, 옥시아미드기 또는 이들 중 어느 것을 포함하는 탄화수소기이다.In addition, B 2 represents -L 3 -(CH 2 ) m3 -L 6 -, -L 3 -(CH 2 ) m3 -L 4 -(CH 2 ) m4 -L 6 - or a single bond, and L 3 is represents an amide bond or a single bond, L 4 represents an ether bond, an amide bond, or a urethane bond, and m3 and m4 each independently represent an integer of 1 to 5. Here, L 6 is an atomic group formed by reaction of a functional group included in Y 1 of the heterobifunctional monodisperse polyethylene glycol represented by the formula (1) and a functional group present in an antibody or drug, preferably an amide bond, Urethane bond, thioether bond, disulfide bond, carbonate bond, ester bond, ether bond, 1H-1,2,3-triazole-1,4-diyl structure, secondary amino group, hydrazide group, oxyamide group, or It is a hydrocarbon group containing any of these.
실시예Example
실시예를 참조로 본 발명을 더욱 구체적으로 설명하지만, 본 발명은 이것으로 한정되는 것은 아니다.The present invention will be more specifically described with reference to Examples, but the present invention is not limited thereto.
1H-NMR 분석에서는, JEOL DATUM Ltd.제 JNM-ECP400 또는 JNM-ECA600를 사용했다. 측정을 위해, 5 mm φ 튜브를 이용하여 중수소화 용매가 CDCl3 또는 CD3OD의 경우는, 내부 표준 물질로서 테트라메틸실란(TMS)을 사용했다.In the 1 H-NMR analysis, JNM-ECP400 or JNM-ECA600 manufactured by JEOL DATUM Ltd. was used. For the measurement, tetramethylsilane (TMS) was used as an internal standard material when the deuterated solvent was CDCl 3 or CD 3 OD using a 5 mm φ tube.
실시예 1Example 1
온도계, 질소 주입 관(nitrogen inlet tube), 교반기, 딘-스타크 관(Dean-stark tube) 및 냉각관을 구비한 500 mL의 4개구 플라스크(four-necked flask)에 트리스히드록시메틸아미노메탄 (30.3 g, 250 mmol), 탄산나트륨 (5.30 g, 50 mmol), 탈수 메탄올 (237 g) 및 벤조니트릴 (5.15 g, 50 mmol)을 채우고, 65℃에서 24시간 동안 반응을 수행했다. 반응 혼합물을 여과하였고, 용매를 감압 하에서 증류 제거한 후, 이소프로필 알코올 및 디클로로메탄을 첨가함으로써 용해하였고, 용액을 10중량%의 식염수로 세정하였다. 유기층을 무수 황산 나트륨으로 건조하였고, 여과 후, 용매를 감압 하에서 증류 제거하였다. 잔사를 THF에 용해하였고, 헥산을 첨가하였고 결정화를 실시한 후, 이어서 여과하는 것에 의해 식 (24)의 화합물을 얻었다.Trishydroxymethylaminomethane (30.3) in a 500 mL four-necked flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-stark tube and cooling tube. g, 250 mmol), sodium carbonate (5.30 g, 50 mmol), dehydrated methanol (237 g) and benzonitrile (5.15 g, 50 mmol) were charged and the reaction was carried out at 65° C. for 24 hours. The reaction mixture was filtered, the solvent was distilled off under reduced pressure, and then dissolved by adding isopropyl alcohol and dichloromethane, and the solution was washed with 10 wt% brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was dissolved in THF, hexane was added and crystallization was carried out, followed by filtration to obtain a compound of formula (24).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
3.06 (2H, brs, -OH),3.06 (2H, brs, -O H ),
3.65-3.81 (4H, dd, >C(CH 2OH)2),3.65-3.81 (4H, dd, >C(C H 2 OH) 2 ),
4.38 (2H, s, -CNO-CH 2 -),4.38 (2H, s, -CNO-C H 2 -),
7.32-7.83 (5H, m, arom. H)7.32-7.83 (5H, m, arom. H )
실시예 2Example 2
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 100 mL의 3개구 플라스크에 도데카에틸렌 글리콜 모노메틸 에테르 (10.4 g, 18.5 mmol), 톨루엔 (52.0 g), 트리에틸아민 (2.44 g, 24.1 mmol) 및 염화 메탄술포닐 (2.34 g, 20.4 mmol)을 채우고, 40℃에서 3시간 반응을 실시하였다. 반응 용액에 디클로로메탄을 첨가함으로써 희석한 후에 물로 세정하였고, 유기층을 무수 황산마그네슘으로 건조하였다. 여과 후, 용매를 감압 하에서 증류 제거하여 식 (25)의 화합물을 얻었다.Dodecaethylene glycol monomethyl ether (10.4 g, 18.5 mmol), toluene (52.0 g), triethylamine in a 100 mL 3-neck flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube. (2.44 g, 24.1 mmol) and methanesulfonyl chloride (2.34 g, 20.4 mmol) were charged, and the reaction was carried out at 40° C. for 3 hours. The reaction solution was diluted by adding dichloromethane, washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a compound of formula (25).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
3.08 (3H, s, -O-SO2-CH 3 ),3.08 (3H, s, -O-SO 2 -C H 3 ),
3.38 (3H, s, -O-CH 3 ),3.38 (3H, s, -OC H 3 ),
3.45-3.85 (46H, m, CH3-O-(CH 2 CH 2O)11-CH 2 CH2-O-SO2-CH3),3.45-3.85 (46H, m, CH 3 -O-(C H 2 C H 2 O) 11 -C H 2 CH 2 -O-SO 2 -CH 3 ),
4.38 (2H, m, -CH 2 -O-SO2-CH3)4.38 (2H, m, -C H 2 -O-SO 2 -CH 3 )
실시예 3Example 3
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 50 mL의 3개구 플라스크에 식 (24)의 화합물 (0.21 g, 1.01 mmol), 탈수 THF (7.70 g), 식 (25)의 화합물 (2.46 g, 3.84 mmol), 1M 3차-부톡시 칼륨 THF 용액 (3.72 g. 4.04 mmol)을 채우고, 50℃에서 4시간 동안 반응을 실시하였다. 그 후 디클로로메탄, 및 25중량% 식염수를 첨가하였고 물로 세정을 실시하였고, 유기층을 무수 황산 나트륨으로 건조하였다. 여과 후, 용매를 감압 하에서 증류 제거하여 식 (26)의 화합물을 얻었다.Compound of formula (24) (0.21 g, 1.01 mmol), dehydrated THF (7.70 g), formula (25) in a 50 mL 3-neck flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube ) (2.46 g, 3.84 mmol) and 1M tert-butoxy potassium THF solution (3.72 g. 4.04 mmol) were charged, and the reaction was carried out at 50°C for 4 hours. Thereafter, dichloromethane and 25 wt% brine were added, followed by washing with water, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the compound of formula (26).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
3.38 (6H, s, -O-CH 3 ),3.38 (6H, s, -OC H 3 ),
3.40-3.75 (100H, m, >C(CH 2O)2-, -O-(CH 2 CH 2O)12-, -CNO-CH 2 -),3.40-3.75 (100H, m, >C(C H 2 O) 2 -, -O-(C H 2 C H 2 O) 12 -, -CNO-C H 2 -),
4.36 (2H, s, -CNO-CH 2 -),4.36 (2H, s, -CNO-C H 2 -),
7.37-7.94 (5H, m, arom. H)7.37-7.94 (5H, m, arom. H )
실시예 4Example 4
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 100 mL 3개구 플라스크에 식 (26)의 화합물 (1.13 g, 0.877 mmol) 및 증류수 (31.1 g)를 첨가하여 용해시켰다. 85% 인산 (0.43 mL)을 첨가하여 pH 1.5로 조정한 후, 50℃에서 3시간 동안 반응을 실시하였다. 그 후 냉각하면서 400g/L 수산화 나트륨 수용액 (5.58 mL)을 첨가한 후, 50℃에서 6시간 동안 반응을 실시하였다. 이어서, 6N 염산을 첨가하여 pH 2.0로 조정한 후, 톨루엔 및 클로로포름을 첨가하고 세정을 실시하였다. 25% 식염수가 되도록 염화나트륨을 첨가한 후, 400g/L 수산화 나트륨 수용액을 이용하여 pH 12.5으로 조정하였다. 톨루엔을 이용하여 추출을 실시하였고, 추출물을 무수 황산 나트륨으로 건조하였다. 여과 후, 용매를 감압 하에서 증류 제거하여 식 (27)의 화합물을 얻었다.The compound of formula (26) (1.13 g, 0.877 mmol) and distilled water (31.1 g) were added and dissolved in a 100 mL three-necked flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube. After adjusting the pH to 1.5 by adding 85% phosphoric acid (0.43 mL), the reaction was carried out at 50° C. for 3 hours. Thereafter, 400 g/L aqueous sodium hydroxide solution (5.58 mL) was added while cooling, and the reaction was carried out at 50° C. for 6 hours. Then, after adding 6N hydrochloric acid to adjust the pH to 2.0, toluene and chloroform were added and washing was performed. After sodium chloride was added so that it became 25% saline, the pH was adjusted to 12.5 using 400 g/L aqueous sodium hydroxide solution. Extraction was performed using toluene, and the extract was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the compound of formula (27).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
3.08 (1H, brs, -OH),3.08 (1H, brs, -O H ),
3.38 (6H, s, -O-CH 3 ),3.38 (6H, s, -OC H 3 ),
3.40-3.80 (102H, m, >C(CH 2O)2-, -O-(CH 2 CH 2O)12-, >CNH2-CH 2 -OH)3.40-3.80 (102H, m, >C(C H 2 O) 2 -, -O-(C H 2 C H 2 O) 12 -, >CNH 2 -C H 2 -OH)
실시예 5Example 5
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 50 mL의 3개구 플라스크에 식 (27)의 화합물 (0.800 g, 0.663 mmol), 6-말레이미도헥사노익산 (0.161 g, 0.762 mmol), DMT-MM (0.263 g, 0.762 mmol), 아세토니트릴 (8.00 g) 및 트리에틸아민 (0.081 g, 0.796 mmol)을 채우고, 25℃에서 7시간 동안 반응을 실시했다. pH 3.0의 구연산 완충액(9.60 g)을 여기에 첨가한 후, 톨루엔을 이용하여 세정을 실시하였다. 클로로포름을 이용하여 추출을 실시한 후, 유기층을 10% 식염수로 세정하였다. 유기층을 무수 황산마그네슘으로 건조하였고, 여과 후, 용매를 감압 하에서 증류 제거하여 식 (28)의 화합물을 얻었다.Compound of formula (27) (0.800 g, 0.663 mmol), 6-maleimidohexanoic acid (0.161 g) in a 50 mL 3-neck flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube , 0.762 mmol), DMT-MM (0.263 g, 0.762 mmol), acetonitrile (8.00 g) and triethylamine (0.081 g, 0.796 mmol) were charged, and the reaction was carried out at 25° C. for 7 hours. A citric acid buffer (9.60 g) having a pH of 3.0 was added thereto, followed by washing with toluene. After extraction with chloroform, the organic layer was washed with 10% brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain the compound of Formula (28).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.31 (2H, m, -CH 2 CH2CH2-CONH-),1.31 (2H, m, -C H 2 CH 2 CH 2 -CONH-),
1.62 (4H, m, -CH 2 CH2CH 2 CH2-CONH-),1.62 (4H, m, -C H 2 CH 2 C H 2 CH 2 -CONH-),
2.18 (2H, t, -CH 2 -CONH-),2.18 (2H, t, -C H 2 -CONH-),
3.38 (6H, s, -O-CH 3 ),3.38 (6H, s, -OC H 3 ),
3.40-3.85 (104H, m, >C(CH 2O)2-, -O-(CH 2 CH 2O)12-, >CNH-CH 2 -OH, -CH 2 -maleimide),3.40-3.85 (104H, m, >C(C H 2 O) 2 -, -O-(C H 2 C H 2 O) 12 -, >CNH-C H 2 -OH, -C H 2 -maleimide) ,
4.62 (1H, t, -OH),4.62 (1H, t, -O H ),
6.23 (1H, s, -CH2-CONH-),6.23 (1H, s, -CH 2 -CON H -),
6.69 (2H, s, -maleimide)6.69 (2H, s, - maleimide )
실시예 6Example 6
교반자를 포함하는 4-mL의 스크류 관(screw tube)에 식 (28)의 화합물(0.050g,0.036mmol), N-메틸모르폴린(0.036g,0.357 mmol), 비스(4-니트로페닐) 카보네이트(0.087g,0.286 mmol) 및 탈수 아세트니트릴(0.281 g)을 첨가하여 질소 분위기 중의, 25℃에서 10시간 동안 반응을 실시했다. 증류수 (0.018 g, 1.00 mmol) 및 N-메틸모르폴린 (0.022 g, 0.214 mmol)을 여기에 첨가하여, 혼합물을 25℃에서 6시간 동안 교반한 후, 디클로로메탄을 이용하여 희석하였다. 혼합물을 pH 3.0의 구연산 완충액을 이용하여 세정한 후, pH 10.0의 붕산 완충액, 25% 식염수를 이용하여 세정을 실시했다. 유기층을 무수 황산 나트륨으로 건조하였고, 여과 후, 용매를 감압 하에서 증류 제거하여 식 (29)의 화합물을 얻었다.In a 4-mL screw tube containing a stirrer, the compound of formula (28) (0.050 g, 0.036 mmol), N-methylmorpholine (0.036 g, 0.357 mmol), and bis (4-nitrophenyl) carbonate (0.087 g, 0.286 mmol) and dehydrated acetonitrile (0.281 g) were added, and the reaction was carried out at 25° C. in a nitrogen atmosphere for 10 hours. Distilled water (0.018 g, 1.00 mmol) and N-methylmorpholine (0.022 g, 0.214 mmol) were added thereto, and the mixture was stirred at 25° C. for 6 hours, and then diluted with dichloromethane. The mixture was washed with a citric acid buffer at pH 3.0, and then washed with a boric acid buffer at pH 10.0 and 25% saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain the compound of formula (29).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.31 (2H, m, -CH 2 CH2CH2-CONH-),1.31 (2H, m, -C H 2 CH 2 CH 2 -CONH-),
1.59 (4H, m, -CH 2 CH2CH 2 CH2-CONH-),1.59 (4H, m, -C H 2 CH 2 C H 2 CH 2 -CONH-),
2.16 (2H, t, -CH 2 -CONH-),2.16 (2H, t, -C H 2 -CONH-),
3.38 (6H, s, -O-CH 3 ),3.38 (6H, s, -OC H 3 ),
3.40-3.85 (102H, m, >C(CH 2O)2-, -O-(CH 2 CH 2O)12-, -CH 2 -maleimide),3.40-3.85 (102H, m, >C(C H 2 O) 2 -, -O-(C H 2 C H 2 O) 12 -, -C H 2 -maleimide),
4.70 (1H, s, >CNH-CH 2 -OCOO-),4.70 (1H, s, >CNH-C H 2 -OCOO-),
6.02 (1H, s, -CH2-CONH-),6.02 (1H, s, -CH 2 -CON H -),
6.69 (2H, s, -maleimide),6.69 (2H, s, - maleimide ),
7.35-8.35 (4H, m, arom. H)7.35-8.35 (4H, m, arom. H )
실시예 7Example 7
교반자를 포함하는 4-mL의 스크류 관에 독소루비신 하이드로클로라이드 (4.08 mg, 7.03 μmol), N,N-디이소프로필아민 (1.98 mg, 14.7 μmol), N,N-디메틸포름아미드 및 식 (29)의 화합물 (10.0 mg, 6.39 μmol)을 첨가하고, 4시간 동안 반응을 실시했다. 디클로로메탄으로 희석한 후, 혼합물을 5 중량%의 인산 이수소 나트륨·12-수화물 수용액을 이용하여 세정한 후, 이온 교환수를 이용하여 세정하였다. 유기층을 무수 황산 나트륨으로 건조하였고, 여과 후, 용매를 감압 하에서 증류 제거 하여, 식 (30)의 약물-링커 화합물을 얻었다.Doxorubicin hydrochloride (4.08 mg, 7.03 μmol), N,N-diisopropylamine (1.98 mg, 14.7 μmol), N,N-dimethylformamide and Formula (29) in a 4-mL screw tube containing a stirrer of the compound (10.0 mg, 6.39 μmol) was added, and the reaction was carried out for 4 hours. After dilution with dichloromethane, the mixture was washed with 5 wt% of sodium dihydrogen phosphate/12-hydrate aqueous solution, followed by washing with ion-exchanged water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a drug-linker compound of Formula (30).
1H-NMR (CD3Cl, 내부 표준 TMS); δ (ppm): 1 H-NMR (CD 3 Cl, internal standard TMS); δ (ppm):
1.23-1.31 (5H, m), 1.55-1.65 (4H, m), 1.75-1.88 (2H, m),1.23-1.31 (5H, m), 1.55-1.65 (4H, m), 1.75-1.88 (2H, m),
2.08 (2H, t), 2.14-2.39 (2H, m), 2.88 (1H, dd),2.08 (2H, t), 2.14-2.39 (2H, m), 2.88 (1H, dd),
3.02 (1H, s), 3.18 (2H, dd), 3.38 (3H, s),3.02 (1H, s), 3.18 (2H, dd), 3.38 (3H, s),
3.41-3.90 (110H, m), 4.03-4.06 (1H, m), 4.09 (3H, s),3.41-3.90 (110H, m), 4.03-4.06 (1H, m), 4.09 (3H, s),
4.12-4.14 (1H, m), 4.22-4.47 (1H, m), 4.65 (1H, s),4.12-4.14 (1H, m), 4.22-4.47 (1H, m), 4.65 (1H, s),
4.77 (2H, d), 5.33 (1H, s), 5.42-5.44 (1H, m),4.77 (2H, d), 5.33 (1H, s), 5.42-5.44 (1H, m),
5.53 (1H, s), 6.16 (1H, s), 6.69 (2H, s),5.53 (1H, s), 6.16 (1H, s), 6.69 (2H, s),
7.41 (1H, d), 7.80 (1H, t), 8.06 (1H, d)7.41 (1H, d), 7.80 (1H, t), 8.06 (1H, d)
실시예 8Example 8
실시예 7로 얻은 식 (30)의 약물-링커 화합물에 대해서, 소수성 상호작용 크로마토그래피(HIC) 컬럼을 이용한 HPLC 측정을 하기의 측정 조건에서 수행하였다. 측정 결과의 차트를 도 1에 나타내었다.For the drug-linker compound of Formula (30) obtained in Example 7, HPLC measurement using a hydrophobic interaction chromatography (HIC) column was performed under the following measurement conditions. A chart of the measurement results is shown in FIG. 1 .
HPLC 장치: Alliance (Waters)HPLC instrument: Alliance (Waters)
컬럼: TSKgel Butyl-NPR (4.6 × 35 mm, 2.5 μm; Tosoh Corp.)Column: TSKgel Butyl-NPR (4.6 × 35 mm, 2.5 μm; Tosoh Corp.)
유속: 0.8 mL/분,flow rate: 0.8 mL/min;
분석 시간: 45 분,Analysis time: 45 min;
컬럼 온도: 25℃,Column temperature: 25°C;
주입량: 100 μL,Injection volume: 100 μL,
검출기: 포토 다이오드 어레이 (측정 파장: 200-600 nm)Detector: photodiode array (measurement wavelength: 200-600 nm)
이동상 A: 1.5 M 황산 암모늄을 포함한, 50 mM 인산나트륨 완충액(pH 7.0)Mobile phase A: 50 mM sodium phosphate buffer (pH 7.0) with 1.5 M ammonium sulfate
이동상 B: 80%의 50 mM 인산 나트륨 완충액 (pH7.0) 및 20%의 이소프로필 알코올을 포함하는 혼합 용액Mobile phase B: a mixed solution containing 80% 50 mM sodium phosphate buffer (pH 7.0) and 20% isopropyl alcohol
경사 프로그램(Gradient program): 0% 내지 0% (0 분 내지 2.5 분), 0% 내지 100% (2.5 분 내지 35 분), 100% 내지 0% (35.1 분 내지 45 분)Gradient program: 0% to 0% (0 min to 2.5 min), 0% to 100% (2.5 min to 35 min), 100% to 0% (35.1 min to 45 min)
실시예 9Example 9
마우스에서 생산된 모노클로날 항-인터류킨-1 베타 항체(0.500 mg, Sigma-Aldrich)를 인산 완충 식염수 (PBS, 0.500 mL)에 용해했다. 이 용액(0.048 mL)을 0.5 mL의 폴리프로필렌제 튜브에 넣고, 여기에 50.0 mM의 에틸렌디아민 테트라아세트산 (EDTA, 0.006 mL) 및 0.800 mM 트리스(2-카르복시메틸)포스핀 하이드로클로라이드 (TCEP) 수용액 (0.006 mL; 항체에 대해서 15 당량)을 첨가하고 혼합물을 37℃에서 1시간 동안 진탕하였다(shaken). 상기 용액에, N,N-디메틸아세트아미드 및 2.50 mM의 식 (30)의 화합물 포함하는 용액(0.007mL; 항체에 대해서 53 당량)을 첨가하고, 그 혼합물을 20℃에서 1시간 동안 추가로 진탕하였다. 2.50 mM N-아세틸 시스테인의 수용액(0.007mL; 항체에 대해서 53 당량)을 첨가하여, 얻어진 혼합물을 20℃에서 1시간 동안 추가로 진탕하였다. PBS (10 mL)를 이용하여 평형화한 NAP-5 컬럼(GE Healthcare Life Science)에 상기에서 얻어진 용액을 충전하였고, PBS로 용출하게 하여, 항체 분획을 분취하였다.A mouse-produced monoclonal anti-interleukin-1 beta antibody (0.500 mg, Sigma-Aldrich) was dissolved in phosphate buffered saline (PBS, 0.500 mL). This solution (0.048 mL) is placed in a 0.5 mL polypropylene tube, to which 50.0 mM ethylenediamine tetraacetic acid (EDTA, 0.006 mL) and 0.800 mM tris(2-carboxymethyl)phosphine hydrochloride (TCEP) aqueous solution (0.006 mL; 15 eq relative to antibody) was added and the mixture was shaken at 37° C. for 1 h. To the solution, a solution containing N,N-dimethylacetamide and 2.50 mM of the compound of formula (30) (0.007 mL; 53 equivalents relative to the antibody) was added, and the mixture was further shaken at 20°C for 1 hour. did. An aqueous solution of 2.50 mM N-acetyl cysteine (0.007 mL; 53 equivalents relative to antibody) was added, and the resulting mixture was further shaken at 20° C. for 1 hour. The solution obtained above was filled in a NAP-5 column (GE Healthcare Life Science) equilibrated using PBS (10 mL), and eluted with PBS, and the antibody fraction was fractionated.
실시예 10Example 10
항체-약물 복합체에 있어서의 항체 당 평균 결합수는, 항체-약물 복합체 수용액의 280 nm 및 495 nm의 2 파장에 있어서의 UV흡광도를 측정한 후에 하기의 계산을 실시하는 것으로, 산출할 수 있다.The average number of bonds per antibody in the antibody-drug complex can be calculated by measuring the UV absorbance at two wavelengths of 280 nm and 495 nm of the aqueous antibody-drug complex aqueous solution and then performing the following calculation.
어떤 파장에 있어서의 전체 흡광도는 계 내에 존재하는 모든 흡수 화학종의 흡광도의 합계와 동일하며(흡광도의 가성성(additivity of absorbance)), 항체와 약물의 복합화 반응 전후에 있어서, 항체 및 약물의 몰 흡광 계수에 변화가 없는 경우를 가정하면, 항체-약물 복합체에 있어서의 항체 농도 및 약물 농도는, 하기의 관계식에서 나타내어진다.The total absorbance at a certain wavelength is equal to the sum of the absorbances of all absorbing species present in the system (additivity of absorbance), and before and after the antibody-drug complex reaction, the moles of antibody and drug Assuming that there is no change in the extinction coefficient, the antibody concentration and the drug concentration in the antibody-drug complex are represented by the following relational equations.
A280 = AD, 280 + AA, 280 = εD, 280 CD + εA, 280 CA 식 (i)A 280 = A D, 280 + A A, 280 = ε D, 280 C D + ε A, 280 C A Equation (i)
A495 = AD, 495 + AA, 495 = εD, 495 CD + εA, 495 CA 식 (ii)A 495 = A D, 495 + A A, 495 = ε D, 495 C D + ε A, 495 C A Equation (ii)
여기서, A280은 280 nm에 있어서의 항체-약물 복합체 수용액의 흡광도를 나타내고, A495는 495 nm에 있어서의 항체-약물 복합체 수용액의 흡광도를 나타내고, AA, 280은 280 nm에 있어서의 항체의 흡광도를 나타내고, AA, 495는 495 nm에 있어서의 항체의 흡광도를 나타내고, AD, 280은 280 nm에 있어서의 약물-링커 화합물의 흡광도를 나타내고, AD, 495는 495 nm에 있어서의 약물-링커 화합물의 흡광도를 나타내고,εA, 280은 280 nm에 있어서의 항체의 몰 흡광 계수를 나타내고,εA, 495는 495 nm에 있어서의 항체의 몰 흡광 계수를 나타내고,εD, 280은 280 nm에 있어서의 약물-링커 화합물의 몰 흡광 계수를 나타내고, εD, 495는 495 nm에 있어서의 약물-링커 화합물의 몰 흡광 계수를 나타내고, CA는 항체-약물 복합체에 있어서의 항체 농도를 나타내고, CD는 항체-약물 복합체에 있어서의 약물 농도를 나타낸다.Here, A 280 represents the absorbance of the antibody-drug complex aqueous solution at 280 nm, A 495 represents the absorbance of the antibody-drug complex aqueous solution at 495 nm, and A A and 280 represent the absorbance of the antibody at 280 nm. Absorbance is shown, A A, 495 shows the absorbance of the antibody at 495 nm, AD , 280 shows the absorbance of the drug-linker compound at 280 nm , AD, 495 shows the drug at 495 nm - represents the absorbance of the linker compound, ε A, 280 represents the molar extinction coefficient of the antibody at 280 nm, ε A, 495 represents the molar extinction coefficient of the antibody at 495 nm, ε D, 280 is 280 represents the molar extinction coefficient of the drug-linker compound in nm, ε D, 495 represents the molar extinction coefficient of the drug-linker compound at 495 nm, CA represents the antibody concentration in the antibody-drug complex , C D represent the drug concentration in the antibody-drug complex.
여기서,εA, 280, εA, 495, εD, 280 및 εD, 495는, 사전에 준비한 값(추정치 또는 화합물의 UV 측정으로부터 얻어진 실측치)이 이용된다. εA, 495는, 통상적으로, 0이다. εD, 280 및 εD, 495는, 이용하는 약물-링커 화합물을 특정 몰 농도에 용해시킨 용액의 흡광도를 측정하는 것으로, 람베르트-비어 법칙(흡광도 = 몰 농도×몰 흡광 계수×셀 광로 길이)에 의해서, 얻을 수 있다. 항체-약물 복합체 수용액의 A280 및 A495를 측정하고, 이러한 값들을 식 (i) 및 식 (ii)에 대입하고 연립 방정식을 푸는 것에 의해서, CA 및 CD를 구할 수 있다. 또한, CD를 CA로 나누는 것으로 항체 당 약물 평균 결합 수를 구할 수 있다.Here, for ε A, 280 , ε A, 495 , ε D, 280 and ε D, 495 , values prepared in advance (estimated values or actual values obtained from UV measurement of compounds) are used. ε A, 495 is usually 0. ε D, 280 and ε D, 495 measure the absorbance of a solution in which the drug-linker compound used is dissolved at a specific molar concentration, and the Lambert-Beer law (absorbance = molar concentration x molar extinction coefficient x cell optical path length) can be obtained by By measuring A 280 and A 495 of the aqueous antibody-drug complex aqueous solution, substituting these values into equations (i) and (ii) and solving the simultaneous equations, CA and C D can be obtained. Also, the average number of drug bonds per antibody can be obtained by dividing C D by C A .
몰 흡광 계수 εA, 280 = 206,999 (추정치), εA, 495 = 0, εD, 280 = 8067 (실측치) 및 εD, 495 = 8121 (실측치)를 이용하여 상기의 연립 방정식을 푼 결과, 항체 당 약물 평균 결합수는 8.4이었다.As a result of solving the above simultaneous equations using the molar extinction coefficients ε A, 280 = 206,999 (estimated value), ε A, 495 = 0, ε D, 280 = 8067 (actual value) and ε D, 495 = 8121 (estimated value), The average number of drug bindings per antibody was 8.4.
실시예 11Example 11
실시예 7로 얻은 식 (30)의 약물-링커 화합물에 대해서, 소수성 상호작용 크로마토그래피(HIC) 컬럼을 이용한 HPLC 측정을 하기의 측정 조건에서 수행하였다. 측정 파장 495 nm에 있어서의 결과의 차트를 도 3에 나타내었다.For the drug-linker compound of Formula (30) obtained in Example 7, HPLC measurement using a hydrophobic interaction chromatography (HIC) column was performed under the following measurement conditions. The chart of the result in the measurement wavelength of 495 nm is shown in FIG.
HPLC 장치: Alliance (Waters)HPLC instrument: Alliance (Waters)
컬럼: TSKgel Butyl-NPR (4.6 × 35 mm, 2.5 μm; Tosoh Corp.)Column: TSKgel Butyl-NPR (4.6 × 35 mm, 2.5 μm; Tosoh Corp.)
유속: 0.8 mL/분,flow rate: 0.8 mL/min;
분석 시간: 45 분,Analysis time: 45 min;
컬럼 온도: 25℃,Column temperature: 25°C;
주입량: 100 μL,Injection volume: 100 μL,
검출기: 자외선-가시광선 분광 광도계 (측정 파장: 495 nm 및 280 nm)Detector: ultraviolet-visible spectrophotometer (measurement wavelengths: 495 nm and 280 nm)
이동상 A: 1.5 M 황산 암모늄을 포함하는 50 mM 인산 나트륨 완충액 (pH 7.0)Mobile phase A: 50 mM sodium phosphate buffer (pH 7.0) with 1.5 M ammonium sulfate
이동상 B: 80%의 50 mM 인산 나트륨 완충액 (PH 7.0) 및 20%의 이소프로필 알코올을 포함하는 혼합 용액.Mobile phase B: a mixed solution containing 80% of 50 mM sodium phosphate buffer (PH 7.0) and 20% of isopropyl alcohol.
경사 프로그램: 0% 내지 0% (0 분 내지 2.5 분), 0% 내지 100% (2.5 분 내지 35 분), 100% 내지 0% (35.1 분 내지 45 분)Gradient Program: 0% to 0% (0 min to 2.5 min), 0% to 100% (2.5 min to 35 min), 100% to 0% (35.1 min to 45 min)
실시예 12Example 12
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 300 mL의 4개구 플라스크에 테트라에틸렌 글리콜 모노메틸 에테르 (23.0 g, 110 mmol), 톨루엔 (115 g), 트리에틸아민 (14.5 g, 143 mmol) 및 염화 메탄술포닐 (13.9 g, 121 mmol)을 채우고, 40℃에서 2시간 반응을 실시했다. 반응 용액에 디클로로메탄을 첨가하여 희석한 후, 물로 세정하였고, 유기층을 무수 황산마그네슘으로 건조하였다. 여과 후, 용매를 감압 하에서 증류 제거하여 식 (31)의 화합물을 얻었다.In a 300 mL 4-necked flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube, tetraethylene glycol monomethyl ether (23.0 g, 110 mmol), toluene (115 g), triethylamine ( 14.5 g, 143 mmol) and methanesulfonyl chloride (13.9 g, 121 mmol) were charged, and the reaction was carried out at 40° C. for 2 hours. The reaction solution was diluted with dichloromethane, washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a compound of formula (31).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
3.08 (3H, s, -O-SO2-CH 3 ),3.08 (3H, s, -O-SO 2 -C H 3 ),
3.38 (3H, s, -O-CH 3 ),3.38 (3H, s, -OC H 3 ),
3.45-3.85 (14H, m, CH3-O-(CH 2 CH 2O)4-CH 2 CH2-O-SO2-CH3),3.45-3.85 (14H, m, CH 3 -O-(C H 2 C H 2 O) 4 -C H 2 CH 2 -O-SO 2 -CH 3 ),
4.38 (2H, m, -CH 2 -O-SO2-CH3)4.38 (2H, m, -C H 2 -O-SO 2 -CH 3 )
실시예 13Example 13
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 500 mL의 4개구 플라스크에 식 (24)의 화합물 (5.00 g, 24.1 mmol), 탈수 THF (138 g), 식 (31)의 화합물 (16.6 g, 57.9 mmol), 1M 3차-부톡시 칼륨 THF 용액 (52.6 g. 33.7 mmol)을 채우고, 50℃에서 4시간 동안 반응을 실시하였다. 그 후 디클로로메탄, 및 25중량% 식염수를 첨가하였고 물로 세정을 실시하였고, 유기층을 무수 황산 나트륨으로 건조하였다. 여과 후, 용매를 감압 하에서 증류 제거하여 식 (32)의 화합물을 얻었다.Compound of formula (24) (5.00 g, 24.1 mmol), dehydrated THF (138 g), formula (31) in a 500 mL four-necked flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube ) (16.6 g, 57.9 mmol) and 1M tert-butoxy potassium THF solution (52.6 g. 33.7 mmol) were charged, and the reaction was carried out at 50° C. for 4 hours. Thereafter, dichloromethane and 25 wt% brine were added, followed by washing with water, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a compound of formula (32).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
3.38 (6H, s, -O-CH 3 ),3.38 (6H, s, -OC H 3 ),
3.40-3.75 (36H, m, >C(CH 2O)2-, -O-(CH 2 CH 2O)4-, -CNO-CH 2 -),3.40-3.75 (36H, m, >C(C H 2 O) 2 -, -O-(C H 2 C H 2 O) 4 -, -CNO-C H 2 -),
4.36 (2H, s, -CNO-CH 2 -),4.36 (2H, s, -CNO-C H 2 -),
7.37-7.94 (5H, m, arom. H)7.37-7.94 (5H, m, arom. H )
실시예 14Example 14
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 500 mL 4개구 플라스크에 식 (32)의 화합물 (12.0 g, 20.4 mmol) 및 증류수 (168 g)를 첨가하여 용해시켰다. 85% 인산 (6.3 mL)을 첨가하여 pH 1.5로 조정한 후, 50℃에서 2시간 동안 반응을 실시하였다. 그 후 냉각하면서 400g/L 수산화 나트륨 수용액 (72.9 mL)을 첨가한 후, 50℃에서 5시간 동안 반응을 실시하였다. 이어서, 6N 염산을 첨가하여 pH 2.0로 조정한 후, 톨루엔 및 클로로포름을 첨가하고 세정을 실시하였다. 25% 식염수가 되도록 염화나트륨을 첨가한 후, 400g/L 수산화 나트륨 수용액을 이용하여 pH 12.5으로 조정하였다. 톨루엔을 이용하여 추출을 실시하였고, 추출물을 무수 황산 나트륨으로 건조하였고, 여과 후, 용매를 감압 하에서 증류 제거하여 식 (33)의 화합물을 얻었다.The compound of formula (32) (12.0 g, 20.4 mmol) and distilled water (168 g) were added and dissolved in a 500 mL four-necked flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube. After adjusting the pH to 1.5 by adding 85% phosphoric acid (6.3 mL), the reaction was carried out at 50° C. for 2 hours. Thereafter, 400 g/L aqueous sodium hydroxide solution (72.9 mL) was added while cooling, and the reaction was carried out at 50° C. for 5 hours. Then, after adding 6N hydrochloric acid to adjust the pH to 2.0, toluene and chloroform were added, followed by washing. After sodium chloride was added so that it became 25% saline, the pH was adjusted to 12.5 using 400 g/L aqueous sodium hydroxide solution. Extraction was carried out using toluene, the extract was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain the compound of formula (33).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
3.08 (1H, brs, -OH),3.08 (1H, brs, -O H ),
3.38 (6H, s, -O-CH 3 ),3.38 (6H, s, -OC H 3 ),
3.40-3.80 (38H, m, >C(CH 2O)2-, -O-(CH 2 CH 2O)4-, >CNH2-CH 2 -OH)3.40-3.80 (38H, m, >C(C H 2 O) 2 -, -O-(C H 2 C H 2 O) 4 -, >CNH 2 -C H 2 -OH)
실시예 15Example 15
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 100 mL 3개구 플라스크에 식 (33)의 화합물 (3.00 g, 5.98 mmol), 6-말레이미도헥사노익산 (1.45 g, 6.88 mmol), DMT-MM (1.90 g, 6.88 mmol), 아세토니트릴 (30.0 g) 및 트리에틸아민 (0.726 g, 7.18 mmol)을 채우고, 25℃에서 5시간 동안 반응을 실시했다. pH 3.0의 구연산 완충액(36.0 g)을 여기에 첨가한 후, 톨루엔을 이용하여 세정을 실시하였다. 클로로포름을 이용하여 추출을 실시한 후, 유기층을 10% 식염수로 세정하였다. 유기층을 무수 황산마그네슘으로 건조하였고, 여과 후, 용매를 감압 하에서 증류 제거하여 식 (34)의 화합물을 얻었다.In a 100 mL three-necked flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube, the compound of formula (33) (3.00 g, 5.98 mmol), 6-maleimidohexanoic acid (1.45 g, 6.88 mmol), DMT-MM (1.90 g, 6.88 mmol), acetonitrile (30.0 g) and triethylamine (0.726 g, 7.18 mmol) were charged, and the reaction was carried out at 25° C. for 5 hours. A citric acid buffer (36.0 g) having a pH of 3.0 was added thereto, followed by washing with toluene. After extraction with chloroform, the organic layer was washed with 10% brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain the compound of formula (34).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.31 (2H, m, -CH 2 CH2CH2-CONH-),1.31 (2H, m, -C H 2 CH 2 CH 2 -CONH-),
1.62 (4H, m, -CH 2 CH2CH 2 CH2-CONH-),1.62 (4H, m, -C H 2 CH 2 C H 2 CH 2 -CONH-),
2.18 (2H, t, -CH 2 -CONH-),2.18 (2H, t, -C H 2 -CONH-),
3.38 (6H, s, -O-CH 3 ),3.38 (6H, s, -OC H 3 ),
3.40-3.85 (40H, m, >C(CH 2O)2-, -O-(CH 2 CH 2O)4-, >CNH-CH 2 -OH, -CH 2 -maleimide),3.40-3.85 (40H, m, >C(C H 2 O) 2 -, -O-(C H 2 C H 2 O) 4 -, >CNH-C H 2 -OH, -C H 2 -maleimide) ,
4.62 (1H, t, -OH),4.62 (1H, t, -O H ),
6.23 (1H, s, -CH2-CONH-),6.23 (1H, s, -CH 2 -CON H -),
6.69 (2H, s, -maleimide)6.69 (2H, s, - maleimide )
실시예 16Example 16
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 50 mL 3개구 플라스크에 식 (34)의 화합물 (2.50 g, 3.60 mmol), N-페닐모르폴린 (1.47 g, 9.00 mmol), p-니트로페닐 클로로포르메이트 (1.45 g, 7.20 mmol) 및 디클로로메탄 (47.7 g)을 첨가하고, 25℃에서 2시간 동안 반응을 실시했다. 여기에 증류수 (0.39 g, 21.6 mmol) 및 N-페닐모르폴린 (1.47 g, 9.00 mmol)를 첨가하고, 혼합물을 25℃에서 6시간 동안 교반한 후, 헥산을 이용하여 희석했다. 그 혼합물을 0.2 M 염산을 이용하여 세정한 후, pH 10의 붕산 완충액, 10% 식염수를 이용하여 세정하였다. 유기층을 무수 황산 나트륨으로 건조하여, 여과 후, 용매를 감압 하에서 증류 제거하였고, 잔사를 아세토니트릴에 용해시켰다. 헥산 및 3차-부탄올을 첨가하여 세정한 후, 용매를 감압 하에서 증류 제거하여 식 (35)의 화합물을 얻었다.Compound of formula (34) (2.50 g, 3.60 mmol), N-phenylmorpholine (1.47 g, 9.00 mmol) in a 50 mL three neck flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube ), p-nitrophenyl chloroformate (1.45 g, 7.20 mmol) and dichloromethane (47.7 g) were added, and the reaction was carried out at 25° C. for 2 hours. Distilled water (0.39 g, 21.6 mmol) and N-phenylmorpholine (1.47 g, 9.00 mmol) were added thereto, and the mixture was stirred at 25° C. for 6 hours, and then diluted with hexane. The mixture was washed with 0.2 M hydrochloric acid and then washed with a boric acid buffer having a pH of 10 and 10% saline. The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was dissolved in acetonitrile. After washing by adding hexane and tert-butanol, the solvent was distilled off under reduced pressure to obtain a compound of formula (35).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.31 (2H, m, -CH 2 CH2CH2-CONH-),1.31 (2H, m, -C H 2 CH 2 CH 2 -CONH-),
1.59 (4H, m, -CH 2 CH2CH 2 CH2-CONH-),1.59 (4H, m, -C H 2 CH 2 C H 2 CH 2 -CONH-),
2.16 (2H, t, -CH 2 -CONH-),2.16 (2H, t, -C H 2 -CONH-),
3.38 (6H, s, -O-CH 3 ),3.38 (6H, s, -OC H 3 ),
3.40-3.85 (38H, m, >C(CH 2O)2-, -O-(CH 2 CH 2O)4-, -CH 2 -maleimide),3.40-3.85 (38H, m, >C(C H 2 O) 2 -, -O-(C H 2 C H 2 O) 4 -, -C H 2 -maleimide),
4.70 (1H, s, >CNH-CH 2 -OCOO-),4.70 (1H, s, >CNH-C H 2 -OCOO-),
6.08 (1H, s, -CH2-CONH-),6.08 (1H, s, -CH 2 -CON H -),
6.69 (2H, s, -maleimide),6.69 (2H, s, - maleimide ),
7.35-8.35 (4H, m, arom. H)7.35-8.35 (4H, m, arom. H )
비교예 1Comparative Example 1
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 100 mL 3개구 플라스크에 2-아미노-2-메틸-1,3-프로판디올 (13.1 g, 125 mmol), 탄산나트륨 (2.65 g, 25 mmol), 탈수 메탄올 (19.8 g) 및 벤조니트릴 (2.58 g, 25 mmol)을 채우고, 실시예 1과 동일한 방식으로 반응 및 정제를 실시하여, 식 (36)의 화합물을 얻었다.2-amino-2-methyl-1,3-propanediol (13.1 g, 125 mmol), sodium carbonate (2.65) in a 100 mL 3-necked flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube. g, 25 mmol), dehydrated methanol (19.8 g) and benzonitrile (2.58 g, 25 mmol) were charged, and the reaction and purification were carried out in the same manner as in Example 1 to obtain the compound of formula (36).
1H-NMR (CD3OD, 내부 표준 TMS); δ (ppm): 1 H-NMR (CD 3 OD, internal standard TMS); δ (ppm):
1.33 (3H, s, >CCH 3 -CH2-OH),1.33 (3H, s, >CC H 3 -CH 2 -OH),
3.49-3.60 (2H, dd, >CCH3-CH 2 -OH),3.49-3.60 (2H, dd, >CCH 3 -C H 2 -OH),
4.10-4.53 (2H, dd, -CNO-CH 2 -),4.10-4.53 (2H, dd, -CNO-C H 2 -),
7.43-7.93 (5H, m, arom. H)7.43-7.93 (5H, m, arom. H )
비교예 2Comparative Example 2
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 50 mL 3개구 플라스크에 식 (36)의 화합물 (0.130 g, 0.680 mmol), 탈수 THF (1.87 g), 식 (25)의 화합물 (0.651 g, 1.02 mmol), 1M 3차-부톡시 칼륨 THF 용액 (0.928 g. 1.02 mmol)을 채우고, 실시예 3과 동일한 방식으로 반응 및 정제를 실시하여, 식 (37)의 화합물을 얻었다.Compound of formula (36) (0.130 g, 0.680 mmol), dehydrated THF (1.87 g), formula (25) in a 50 mL three neck flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube (0.651 g, 1.02 mmol), 1M tert-butoxy potassium THF solution (0.928 g. 1.02 mmol) was charged, and reaction and purification were carried out in the same manner as in Example 3 to obtain the compound of formula (37) got it
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.37 (3H, s, >CCH 3 -CH2-O-CH2-),1.37 (3H, s, >CC H 3 -CH 2 -O-CH 2 -),
3.38 (3H, s, -O-CH 3 ),3.38 (3H, s, -OC H 3 ),
3.40-3.80 (50H, m, >CCH3-CH 2 -O-CH2-, -O-(CH 2 CH 2O)12-, -CNO-CH 2 -),3.40-3.80 (50H, m, >CCH 3 -C H 2 -O-CH 2 -, -O-(C H 2 C H 2 O) 12 -, -CNO-C H 2 -),
4.01-4.47 (2H, dd, -CNO-CH 2 -),4.01-4.47 (2H, dd, -CNO-C H 2 -),
7.38-7.95 (5H, m, arom. H)7.38-7.95 (5H, m, arom. H )
비교예 3Comparative Example 3
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 50 mL 3개구 플라스크에 식 (37)의 화합물 (0.160 g, 0.218 mmol) 및 증류수 (4.40 g)를 첨가하여, 용해시켰다. 85% 인산 (0.11 mL)을 첨가하여 pH 1.5로 조정한 후, 50℃에서 6시간 동안 반응을 실시했다. 그 다음 냉각하면서 400g/L 수산화 나트륨 수용액 (1.40 mL)을 첨가한 후, 50℃에서 5시간 동안 반응을 실시했다. 이어서, 6N 염산을 첨가하여 pH 2.0로 조정한 후, 톨루엔 및 클로로포름을 첨가하고 세정을 실시했다. 이후, 실시예 4와 동일한 방식으로 정제를 실시하여, 식 (38)의 화합물을 얻었다.To a 50 mL three-necked flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube, the compound of formula (37) (0.160 g, 0.218 mmol) and distilled water (4.40 g) were added and dissolved. . After adjusting the pH to 1.5 by adding 85% phosphoric acid (0.11 mL), the reaction was carried out at 50° C. for 6 hours. Then, 400 g/L aqueous sodium hydroxide solution (1.40 mL) was added while cooling, and the reaction was carried out at 50° C. for 5 hours. Next, after adding 6N hydrochloric acid to adjust pH to 2.0, toluene and chloroform were added and washing|cleaning was performed. Thereafter, purification was carried out in the same manner as in Example 4 to obtain a compound of Formula (38).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.03 (3H, s, >CCH 3 -CH2-O-),1.03 (3H, s, >CC H 3 -CH 2 -O-),
2.91 (1H, brs, -OH),2.91 (1H, brs, -O H ),
3.38 (3H, s, -O-CH 3 ),3.38 (3H, s, -OC H 3 ),
3.00-3.85 (52H, m, >CCH3-CH 2 -O-CH2-, -O-(CH 2 CH 2O)12-, >CCH3-CH 2 -OH)3.00-3.85 (52H, m, >CCH 3 -C H 2 -O-CH 2 -, -O-(C H 2 C H 2 O) 12 -, >CCH 3 -C H 2 -OH)
비교예 4Comparative Example 4
교반자를 포함하는 4-mL의 스크류 관에 식 (38)의 화합물 (0.0920 g, 0.142 mmol), 6-말레이미도헥사노익산 (0.0345 g, 0.163 mmol), DMT-MM (0.0564 g, 0.163 mmol), 아세토니트릴 (0.980 g) 및 트리에틸아민 (0.0172 g, 0.170 mmol)을 채우고, 25℃에서 5시간 동안 반응을 실시했다. pH 3.0의 구연산 완충액(1.10 g)을 첨가한 후, 톨루엔을 이용하여 세정을 실시했다. 이후, 실시예 5와 동일한 방식으로 정제를 실시하여, 식 (39)의 화합물을 얻었다.Compound of formula (38) (0.0920 g, 0.142 mmol), 6-maleimidohexanoic acid (0.0345 g, 0.163 mmol), DMT-MM (0.0564 g, 0.163 mmol) in a 4-mL screw tube containing a stirrer , acetonitrile (0.980 g) and triethylamine (0.0172 g, 0.170 mmol) were charged, and the reaction was carried out at 25° C. for 5 hours. After adding a citric acid buffer (1.10 g) having a pH of 3.0, washing was performed using toluene. Thereafter, purification was carried out in the same manner as in Example 5 to obtain a compound of formula (39).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.27 (3H, s, >CCH 3 -CH2-O-), 1.32 (2H, m, -CH 2 CH2CH2-CONH-),1.27 (3H, s, >CC H 3 -CH 2 -O-), 1.32 (2H, m, -C H 2 CH 2 CH 2 -CONH-),
1.63 (4H, m, -CH 2 CH2CH 2 CH2-CONH-), 2.18 (2H, t, -CH 2 -CONH-),1.63 (4H, m, -C H 2 CH 2 C H 2 CH 2 -CONH-), 2.18 (2H, t, -C H 2 -CONH-),
3.38 (3H, s, -O-CH 3 ),3.38 (3H, s, -OC H 3 ),
3.40-3.80 (54H, m, >CCH3-CH 2 -O-CH2-, -O-(CH 2 CH 2O)12-, >CCH3-CH 2 -OH, -CH 2 -maleimide),3.40-3.80 (54H, m, >CCH 3 -C H 2 -O-CH 2 -, -O-(C H 2 C H 2 O) 12 -, >CCH 3 -C H 2 -OH, -C H 2 -maleimide),
4.62 (1H, brs, -OH), 6.20 (1H, s, -CH2-CONH-),4.62 (1H, brs, -O H ), 6.20 (1H, s, -CH 2 -CON H -),
6.69 (2H, s, -maleimide)6.69 (2H, s, - maleimide )
비교예 5Comparative Example 5
교반자를 포함하는 4-mL의 스크류 관에 식 (39)의 화합물 (0.050 g, 0.0595 mmol), N-메틸모르폴린 (0.0601 g, 0.595 mmol), 비스(4-니트로페닐) 카보네이트 (0.145 g, 0.476 mmol) 및 탈수 아세토니트릴 (0.467g)을 첨가하고, 질소 분위기에서, 25℃에서 4시간 동안 반응을 실시했다. 증류수 (0.030 g, 1.67 mmol) 및 N-메틸모르폴린 (0.0361 g, 0.357 mmol)를 첨가하고 25℃에서 6시간 동안 교반한 후, 디클로로메탄을 이용하여 희석했다. 이후, 실시예 5와 동일한 방식으로 정제를 실시하여, 식 (40)의 화합물을 얻었다.In a 4-mL screw tube containing a stirrer, the compound of formula (39) (0.050 g, 0.0595 mmol), N-methylmorpholine (0.0601 g, 0.595 mmol), bis(4-nitrophenyl) carbonate (0.145 g, 0.476 mmol) and dehydrated acetonitrile (0.467 g) were added, and the reaction was carried out at 25° C. for 4 hours in a nitrogen atmosphere. Distilled water (0.030 g, 1.67 mmol) and N-methylmorpholine (0.0361 g, 0.357 mmol) were added and stirred at 25° C. for 6 hours, followed by dilution with dichloromethane. Thereafter, purification was carried out in the same manner as in Example 5 to obtain a compound of Formula (40).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.32 (2H, m, -CH 2 CH2CH2-CONH-), 1.45 (3H, s, >CCH 3 -CH2-O-),1.32 (2H, m, -C H 2 CH 2 CH 2 -CONH-), 1.45 (3H, s, >CC H 3 -CH 2 -O-),
1.60 (4H, m, -CH 2 CH2CH 2 CH2-CONH-), 2.15 (2H, t, -CH 2 -CONH-),1.60 (4H, m, -C H 2 CH 2 C H 2 CH 2 -CONH-), 2.15 (2H, t, -C H 2 -CONH-),
3.38 (6H, s, -O-CH 3 ),3.38 (6H, s, -OC H 3 ),
3.41-3.80 (52H, m, >CCH3-CH 2 -O-CH2-, -O-(CH 2 CH 2O)12-, -CH 2 -maleimide),3.41-3.80 (52H, m, >CCH 3 -C H 2 -O-CH 2 -, -O-(C H 2 C H 2 O) 12 -, -C H 2 -maleimide),
4.51-4.59 (2H, dd, >CCH3-CH 2 -OCOO-),4.51-4.59 (2H, dd, >CCH 3 -C H 2 -OCOO-),
5.92 (1H, s, -CH2-CONH-), 6.68 (2H, s, -maleimide),5.92 (1H, s, -CH 2 -CON H -), 6.68 (2H, s, - maleimide ),
7.39-8.29 (4H, m, arom. H)7.39-8.29 (4H, m, arom. H )
비교예 6Comparative Example 6
교반자를 포함하는 4-mL 스크류 관에 독소루비신 하이드로클로라이드 (6.34 mg, 10.9 μmol), N,N-디이소프로필아민 (2.95 mg, 22.9 μmol), N,N-디메틸포름아미드 및 식 (40)의 화합물 (10.0mg, 9.94 μmol)을 첨가하고, 4시간 동안 반응을 실시했다. 디클로로메탄으로 희석한 후, 혼합물을 5 중량%의 인산 이수소 나트륨·12-수화물 수용액을 이용하여 세정한 후, 이온 교환수를 이용하여 세정하였다. 유기층을 무수 황산 나트륨으로 건조하였고, 여과 후, 용매를 감압 하에서 증류 제거 하여, 식 (41)의 약물-링커 화합물을 얻었다.Doxorubicin hydrochloride (6.34 mg, 10.9 μmol), N,N-diisopropylamine (2.95 mg, 22.9 μmol), N,N-dimethylformamide and formula (40) in a 4-mL screw tube containing a stirrer Compound (10.0 mg, 9.94 μmol) was added, and the reaction was carried out for 4 hours. After dilution with dichloromethane, the mixture was washed with 5 wt% of sodium dihydrogen phosphate/12-hydrate aqueous solution, followed by washing with ion-exchanged water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a drug-linker compound of Formula (41).
1H-NMR (CD3Cl, 내부 표준 TMS); δ (ppm): 1 H-NMR (CD 3 Cl, internal standard TMS); δ (ppm):
1.25-1.34 (8H, m), 1.55-1.65 (4H, m), 1.75-1.88 (2H, m),1.25-1.34 (8H, m), 1.55-1.65 (4H, m), 1.75-1.88 (2H, m),
2.06-2.10 (2H, m), 2.16-2.38 (2H, m), 2.88 (1H, dd),2.06-2.10 (2H, m), 2.16-2.38 (2H, m), 2.88 (1H, dd),
3.00 (1H, s), 3.18 (2H, dd), 3.38 (3H, s),3.00 (1H, s), 3.18 (2H, dd), 3.38 (3H, s),
3.41-3.90 (60H, m), 4.03-4.06 (1H, m), 4.09 (3H, s),3.41-3.90 (60H, m), 4.03-4.06 (1H, m), 4.09 (3H, s),
4.12-4.14 (1H, m), 4.61 (1H, s), 4.77 (2H, d),4.12-4.14 (1H, m), 4.61 (1H, s), 4.77 (2H, d),
5.32 (1H, s), 5.43-5.48 (1H, m), 5.53 (1H, s),5.32 (1H, s), 5.43-5.48 (1H, m), 5.53 (1H, s),
6.06 (1H, d), 6.68 (2H, s), 7.41 (1H, d),6.06 (1H, d), 6.68 (2H, s), 7.41 (1H, d),
7.80 (1H, t), 8.06 (1H, d)7.80 (1H, t), 8.06 (1H, d)
비교예 7Comparative Example 7
비교예 6으로 얻은 식 (41)의 약물-링커 화합물에 대해서, 소수성 상호작용 크로마토그래피(HIC) 컬럼을 이용한 HPLC 측정을 실시예 8과 동일한 측정 조건 하에서 실시하였다. 측정 결과의 차트를 도 2에 나타내었다.For the drug-linker compound of Formula (41) obtained in Comparative Example 6, HPLC measurement using a hydrophobic interaction chromatography (HIC) column was performed under the same measurement conditions as in Example 8. A chart of the measurement results is shown in FIG. 2 .
비교예 8Comparative Example 8
마우스에서 생산된 모노클로날 항-인터류킨-1 베타 항체(0.500 mg, Sigma-Aldrich)를 인산 완충 식염수 (PBS, 0.500 mL)에 용해했다. 이 용액(0.048 mL)을 0.5 mL의 폴리프로필렌제 튜브에 넣고, 여기에 50.0 mM의 에틸렌디아민 테트라아세트산 (EDTA, 0.006 mL) 및 0.800 mM 트리스(2-카르복시메틸)포스핀 하이드로클로라이드 (TCEP) 수용액 (0.006 mL; 항체에 대해서 15 당량)을 첨가하고 혼합물을 37℃에서 1시간 동안 진탕하였다. 상기 용액에, N,N-디메틸아세트아미드 및 2.50 mM의 식 (41)의 화합물(0.007 mL; 항체에 대해서 53 당량)을 첨가하고, 그 혼합물을 20℃에서 1시간 동안 추가로 진탕하였다. 2.50 mM N-아세틸 시스테인 (0.007 mL; 항체에 대해서 53 당량) 용액을 첨가하여, 얻어진 혼합물을 20℃에서 1시간 동안 추가로 진탕하였다. PBS (10 mL)를 이용하여 평형화한 NAP-5 컬럼 (GE Healthcare Life Science)에 상기에서 얻어진 용액을 충전하였고, PBS로 용출하게 하여, 항체 분획을 분취하였다.A mouse-produced monoclonal anti-interleukin-1 beta antibody (0.500 mg, Sigma-Aldrich) was dissolved in phosphate buffered saline (PBS, 0.500 mL). This solution (0.048 mL) is placed in a 0.5 mL polypropylene tube, to which 50.0 mM ethylenediamine tetraacetic acid (EDTA, 0.006 mL) and 0.800 mM tris(2-carboxymethyl)phosphine hydrochloride (TCEP) aqueous solution (0.006 mL; 15 equiv for antibody) was added and the mixture was shaken at 37° C. for 1 h. To this solution, N,N-dimethylacetamide and 2.50 mM of the compound of formula (41) (0.007 mL; 53 equivalents for antibody) were added, and the mixture was further shaken at 20° C. for 1 hour. A solution of 2.50 mM N-acetyl cysteine (0.007 mL; 53 equivalents for antibody) was added and the resulting mixture was further shaken at 20° C. for 1 h. A NAP-5 column (GE Healthcare Life Science) equilibrated with PBS (10 mL) was filled with the solution obtained above, and eluted with PBS, and antibody fractions were fractionated.
비교예 9Comparative Example 9
실시예 10과 동일한 방법에 의해 약물 평균 결합수를 산출하였고, 항체 당 약물 평균 결합수는 8.5이었다.The average drug binding number was calculated by the same method as in Example 10, and the average drug binding number per antibody was 8.5.
비교예 10Comparative Example 10
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 50 mL 3개구 플라스크에 테트라코사에틸렌 글리콜 모노메틸 에테르 (2.05 g, 1.88 mmol), 톨루엔 (10.3 g), 트리에틸아민 (0.552 g, 5.45 mmol) 및 염화 메탄술포닐 (0.478 g, 4.17 mmol)을 채우고, 25℃에서 8시간 동안 반응을 실시했다. 반응 용액에 디클로로메탄을 첨가하여 희석한 후에 물로 세정하였고, 유기층을 무수 황산마그네슘으로 건조하였다. 여과 후, 용매를 감압 하에서 증류 제거하여 식 (42)의 화합물을 얻었다.Tetracosaethylene glycol monomethyl ether (2.05 g, 1.88 mmol), toluene (10.3 g), triethylamine ( 0.552 g, 5.45 mmol) and methanesulfonyl chloride (0.478 g, 4.17 mmol) were charged and the reaction was carried out at 25° C. for 8 hours. The reaction solution was diluted with dichloromethane and washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a compound of formula (42).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
3.09 (3H, s, -O-SO2-CH 3 ),3.09 (3H, s, -O-SO 2 -C H 3 ),
3.38 (3H, s, -O-CH 3 ),3.38 (3H, s, -OC H 3 ),
3.45-3.85 (94H, m, CH3-O-(CH 2 CH 2O)23-CH 2 CH2-O-SO2-CH3),3.45-3.85 (94H, m, CH 3 -O-(C H 2 C H 2 O) 23 -C H 2 CH 2 -O-SO 2 -CH 3 ),
4.38 (2H, m, -CH 2 -O-SO2-CH3)4.38 (2H, m, -C H 2 -O-SO 2 -CH 3 )
비교예 11Comparative Example 11
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 50 mL 3개구 플라스크에 식 (36)의 화합물 (0.174 g, 0.910 mmol), 탈수 THF (2.86 g), 식 (42)의 화합물 (1.38 g, 1.18 mmol), 1M 3차-부톡시 칼륨 THF 용액 (1.82 g. 2.00 mmol)를 채우고, 실시예 3과 동일한 방식으로 반응 및 정제를 실시하여, 식 (43)의 화합물을 얻었다.Compound of formula (36) (0.174 g, 0.910 mmol), dehydrated THF (2.86 g), formula (42) in a 50 mL three neck flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube (1.38 g, 1.18 mmol), 1M tert-butoxy potassium THF solution (1.82 g. 2.00 mmol) was charged, and reaction and purification were carried out in the same manner as in Example 3 to obtain the compound of formula (43) got it
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.37 (3H, s, >CCH 3 -CH2-O-CH2-),1.37 (3H, s, >CC H 3 -CH 2 -O-CH 2 -),
3.38 (3H, s, -O-CH 3 ),3.38 (3H, s, -OC H 3 ),
3.40-3.80 (98H, m, >CCH3-CH 2 -O-CH2-, -O-(CH 2 CH 2O)24-),3.40-3.80 (98H, m, >CCH 3 -C H 2 -O-CH 2 -, -O-(C H 2 C H 2 O) 24 -),
4.01-4.47 (2H, dd, -CNO-CH 2 -),4.01-4.47 (2H, dd, -CNO-C H 2 -),
7.38-7.95 (5H, m, arom. H)7.38-7.95 (5H, m, arom. H )
비교예 12Comparative Example 12
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 50 mL 3개구 플라스크에 식 (43)의 화합물 (0.909 g, 0.720 mmol) 및 증류수 (25.0 g)를 첨가하여 용해시켰다. 85% 인산 (0.250 mL)을 첨가하여 pH 1.5로 조정한 후, 50℃에서 6시간 동안 반응을 실시하였다. 그 후 냉각하면서 400g/L 수산화 나트륨 수용액 (7.63 mL)을 첨가한 후, 50℃에서 10시간 동안 반응을 실시하였다. 이어서, 6N 염산을 첨가하여 pH 2.0로 조정한 후, 톨루엔 및 클로로포름을 첨가하고 세정을 실시하였다. 이후, 실시예 4와 동일한 방식으로 정제를 실시하여, 식 (44)의 화합물을 얻었다.The compound of formula (43) (0.909 g, 0.720 mmol) and distilled water (25.0 g) were added and dissolved in a 50 mL three-necked flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube. After adding 85% phosphoric acid (0.250 mL) to adjust the pH to 1.5, the reaction was carried out at 50° C. for 6 hours. Thereafter, 400 g/L aqueous sodium hydroxide solution (7.63 mL) was added while cooling, and the reaction was carried out at 50° C. for 10 hours. Then, after adding 6N hydrochloric acid to adjust the pH to 2.0, toluene and chloroform were added and washing was performed. Thereafter, purification was carried out in the same manner as in Example 4 to obtain a compound of formula (44).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.03 (3H, s, >CCH 3 -CH2-O-),1.03 (3H, s, >CC H 3 -CH 2 -O-),
3.00 (1H, brs, -OH),3.00 (1H, brs, -O H ),
3.38 (3H, s, -O-CH 3 ),3.38 (3H, s, -OC H 3 ),
3.00-3.85 (100H, m, >CCH3-CH 2 -O-CH2-, -O-(CH 2 CH 2O)24-, >CCH3-CH 2 -OH)3.00-3.85 (100H, m, >CCH 3 -C H 2 -O-CH 2 -, -O-(C H 2 C H 2 O) 24 -, >CCH 3 -C H 2 -OH)
비교예 13Comparative Example 13
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 50 mL의 3개구 플라스크에 식 (44)의 화합물 (0.729 g, 0.620 mmol), 6-말레이미도헥사노익산 (0.164 g, 0.775 mmol), DMT-MM (0.214 g, 0.775 mmol), 아세토니트릴 (7.29 g) 및 트리에틸아민 (0.082 g, 0.806 mmol)을 채우고, 25℃에서 3시간 동안 반응을 실시했다. pH 3.0의 구연산 완충액(8.75 g)을 여기에 첨가한 후, 톨루엔을 이용하여 세정을 실시하였다. 이후, 실시예 5와 동일한 방식으로 정제를 실시하여, 식 (45)의 화합물을 얻었다.Compound of formula (44) (0.729 g, 0.620 mmol), 6-maleimidohexanoic acid (0.164 g) in a 50 mL 3-necked flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube , 0.775 mmol), DMT-MM (0.214 g, 0.775 mmol), acetonitrile (7.29 g) and triethylamine (0.082 g, 0.806 mmol) were charged, and the reaction was carried out at 25° C. for 3 hours. A citric acid buffer (8.75 g) of pH 3.0 was added thereto, followed by washing with toluene. Thereafter, purification was carried out in the same manner as in Example 5 to obtain a compound of formula (45).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.23 (3H, s, >CCH 3 -CH2-O-),1.23 (3H, s, >CC H 3 -CH 2 -O-),
1.32 (2H, m, -CH 2 CH2CH2-CONH-),1.32 (2H, m, -C H 2 CH 2 CH 2 -CONH-),
1.63 (4H, m, -CH 2 CH2CH 2 CH2-CONH-),1.63 (4H, m, -C H 2 CH 2 C H 2 CH 2 -CONH-),
2.18 (2H, t, -CH 2 -CONH-),2.18 (2H, t, -C H 2 -CONH-),
3.38 (3H, s, -O-CH 3 ),3.38 (3H, s, -OC H 3 ),
3.40-3.80 (102H, m, >CCH3-CH 2 -O-CH2-, -O-(CH 2 CH 2O)24-, >CCH3-CH 2 -OH, -CH 2 -maleimide),3.40-3.80 (102H, m, >CCH 3 -C H 2 -O-CH 2 -, -O-(C H 2 C H 2 O) 24 -, >CCH 3 -C H 2 -OH, -C H 2 -maleimide),
4.71 (1H, brs, -OH),4.71 (1H, brs, -O H ),
6.26 (1H, s, -CH2-CONH-),6.26 (1H, s, -CH 2 -CON H -),
6.69 (2H, s, -maleimide)6.69 (2H, s, - maleimide )
비교예 14Comparative Example 14
온도계, 질소 주입 관, 교반자, 딘-스타크 관 및 냉각관을 구비한 50 mL 3개구 플라스크에 식 (45)의 화합물 (0.600 g, 0.438 mmol), N-페닐모르폴린 (0.179 g, 1.10 mmol), p-니트로페닐 클로로포르메이트 (0.177 g, 0.876 mmol) 및 디클로로메탄 (5.81 g)을 첨가하고, 25℃에서 3시간 동안 반응을 실시했다. 여기에 증류수 (0.047 g, 2.63 mmol) 및 N-페닐모르폴린 (0.179 g, 1.10 mmol)을 첨가하고, 혼합물을 25℃에서 6시간 동안 교반한 후, 헥산을 이용하여 희석했다. 이후, 실시예 16과 동일한 방식으로 정제를 실시하여, 식 (46)의 화합물을 얻었다.Compound of formula (45) (0.600 g, 0.438 mmol), N-phenylmorpholine (0.179 g, 1.10 mmol) in a 50 mL three neck flask equipped with a thermometer, nitrogen inlet tube, stirrer, Dean-Stark tube and cooling tube ), p-nitrophenyl chloroformate (0.177 g, 0.876 mmol) and dichloromethane (5.81 g) were added, and the reaction was carried out at 25° C. for 3 hours. Distilled water (0.047 g, 2.63 mmol) and N-phenylmorpholine (0.179 g, 1.10 mmol) were added thereto, and the mixture was stirred at 25° C. for 6 hours, and then diluted with hexane. Thereafter, purification was carried out in the same manner as in Example 16 to obtain a compound of formula (46).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.28 (2H, m, -CH 2 CH2CH2-CONH-),1.28 (2H, m, -C H 2 CH 2 CH 2 -CONH-),
1.41 (3H, s, >CCH 3 -CH2-O-),1.41 (3H, s, >CC H 3 -CH 2 -O-),
1.63 (4H, m, -CH 2 CH2CH 2 CH2-CONH-),1.63 (4H, m, -C H 2 CH 2 C H 2 CH 2 -CONH-),
2.15 (2H, t, -CH 2 -CONH-),2.15 (2H, t, -C H 2 -CONH-),
3.38 (3H, s, -O-CH 3 ),3.38 (3H, s, -OC H 3 ),
3.41-3.80 (100H, m, >CCH3-CH 2 -O-CH2-, -O-(CH 2 CH 2O)24-, -CH 2 -maleimide),3.41-3.80 (100H, m, >CCH 3 -C H 2 -O-CH 2 -, -O-(C H 2 C H 2 O) 24 -, -C H 2 -maleimide),
4.51-4.60 (2H, dd, >CCH3-CH 2 -OCOO-),4.51-4.60 (2H, dd, >CCH 3 -C H 2 -OCOO-),
6.01 (1H, s, -CH2-CONH-),6.01 (1H, s, -CH 2 -CON H -),
6.69 (2H, s, -maleimide),6.69 (2H, s, - maleimide ),
7.38-8.36 (4H, m, arom. H)7.38-8.36 (4H, m, arom. H )
비교예 15Comparative Example 15
교반자를 포함하는 4-mL의 스크류 관에 독소루비신 하이드로클로라이드 (5.40 mg, 9.31 μmol), N,N-디이소프로필아민 (2.51 mg, 19.4 μmol), N,N-디메틸포름아미드 및 식 (35)의 화합물 (13.0mg, 8.47 μmol)을 첨가하고, 4시간 동안 반응을 실시했다. 이후, 실시예 7과 동일한 방식으로 정제를 실시하여, 식 (47)의 약물-링커 화합물을 얻었다.Doxorubicin hydrochloride (5.40 mg, 9.31 μmol), N,N-diisopropylamine (2.51 mg, 19.4 μmol), N,N-dimethylformamide and formula (35) in a 4-mL screw tube containing a stirrer of the compound (13.0 mg, 8.47 μmol) was added, and the reaction was carried out for 4 hours. Thereafter, purification was carried out in the same manner as in Example 7, to obtain a drug-linker compound of Formula (47).
1H-NMR (CDCl3, 내부 표준 TMS); δ (ppm): 1 H-NMR (CDCl 3 , internal standard TMS); δ (ppm):
1.25-1.34 (8H, m), 1.55-1.65 (4H, m), 1.75-1.88 (2H, m),1.25-1.34 (8H, m), 1.55-1.65 (4H, m), 1.75-1.88 (2H, m),
2.06-2.10 (2H, m), 2.16-2.38 (2H, m), 2.88 (1H, dd),2.06-2.10 (2H, m), 2.16-2.38 (2H, m), 2.88 (1H, dd),
3.00 (1H, s), 3.18 (2H, dd), 3.38 (3H, s),3.00 (1H, s), 3.18 (2H, dd), 3.38 (3H, s),
3.41-3.90 (103H, m), 4.03-4.06 (1H, m),3.41-3.90 (103H, m), 4.03-4.06 (1H, m),
4.09 (3H, s), 4.12-4.14 (1H, m), 4.61 (1H, s),4.09 (3H, s), 4.12-4.14 (1H, m), 4.61 (1H, s),
4.77 (2H, d), 5.32 (1H, s), 5.43-5.48 (1H, m),4.77 (2H, d), 5.32 (1H, s), 5.43-5.48 (1H, m),
5.53 (1H, s), 6.06 (1H, d), 6.68 (2H, s),5.53 (1H, s), 6.06 (1H, d), 6.68 (2H, s),
7.41 (1H, d), 7.80 (1H, t), 8.06 (1H, d)7.41 (1H, d), 7.80 (1H, t), 8.06 (1H, d)
비교예 16Comparative Example 16
비교예 6으로 얻은 식 (41)의 약물-링커 화합물에 대해서, 소수성 상호작용 크로마토그래피 (HIC) 컬럼을 이용한 HPLC 측정을 실시예 11과 동일한 측정 조건에서 수행하였다. 측정 파장 495 nm에 있어서의 결과의 차트를 도 4에 나타내었다.For the drug-linker compound of Formula (41) obtained in Comparative Example 6, HPLC measurement using a hydrophobic interaction chromatography (HIC) column was performed under the same measurement conditions as in Example 11. The chart of the result in the measurement wavelength of 495 nm is shown in FIG.
비교예 17Comparative Example 17
비교예 15로 얻은 식 (47)의 약물-링커 화합물에 대해서, 소수성 상호작용 크로마토그래피(HIC) 컬럼을 이용한 HPLC 측정을 실시예 11과 동일한 측정 조건에서 수행하였다. 측정 파장 495 nm에 있어서의 결과의 차트를 도 5에 나타냈다.For the drug-linker compound of Formula (47) obtained in Comparative Example 15, HPLC measurement using a hydrophobic interaction chromatography (HIC) column was performed under the same measurement conditions as in Example 11. The chart of the result in the measurement wavelength of 495 nm was shown in FIG.
식 (30)의 약물-링커 화합물은, 도 1의 차트의 보유 시간 14.2분에 검출되었다. 한편, 식 (41)의 약물-링커 화합물은, 도 2의 차트의 보유 시간 15.3분에 검출되었다. 따라서, 보유 시간이 짧은 전자의 약물-링커 화합물이 소수성이 낮은 것으로부터, 본 발명의 헤테로이관능성 단분산 폴리에틸렌 글리콜은, 약물의 소수성을 효과적으로 차폐할 수 있는 것으로 나타났다.The drug-linker compound of formula (30) was detected at a retention time of 14.2 minutes in the chart of FIG. 1 . On the other hand, the drug-linker compound of formula (41) was detected at 15.3 minutes of retention time in the chart of FIG. Therefore, from the low hydrophobicity of the former drug-linker compound with a short retention time, it was shown that the heterobifunctional monodisperse polyethylene glycol of the present invention can effectively mask the hydrophobicity of a drug.
비교예에서, 식 (41)의 약물-링커 화합물은, 도 4의 차트의 보유 시간 14.3분에 검출되었고, 식 (47)의 약물-링커 화합물은, 도 5의 차트의 보유 시간 14.3분에 검출되어 단분산 폴리에틸렌 글리콜의 쇄장에 상관없이 동일한 정도의 보유 시간이 되었다. 한편, 본 발명에 따른 식 (30)의 약물-링커 화합물은, 도 3의 차트의 보유 시간 13.2분에 검출되었다. 따라서, 보유 시간이 짧은 식 (30)의 약물-링커 화합물이 소수성이 낮은 것으로부터, 본 발명의 헤테로이관능성 단분산 폴리에틸렌 글리콜은, 약물의 소수성을 효과적으로 차폐할 수 있는 것으로 나타났다.In the comparative example, the drug-linker compound of Formula (41) was detected at 14.3 minutes of retention time in the chart of FIG. 4, and the drug-linker compound of Formula (47) was detected at 14.3 minutes of retention time of the chart of FIG. 5 Thus, the retention time was the same regardless of the chain length of the monodisperse polyethylene glycol. On the other hand, the drug-linker compound of Formula (30) according to the present invention was detected at a retention time of 13.2 minutes in the chart of FIG. 3 . Therefore, from the low hydrophobicity of the drug-linker compound of Formula (30) with a short retention time, it was shown that the heterobifunctional monodisperse polyethylene glycol of the present invention can effectively mask the hydrophobicity of a drug.
본 발명을 특정의 실시 형태를 참조로 하여 상세하게 설명하였지만, 본 발명의 사상과 범위를 벗어나지 않고 다양한 변경 및 수정이 가능하다는 것은, 당업자에게 자명할 것이다.Although the present invention has been described in detail with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.
또한, 본 출원은, 2017년 3월 30일자로 출원된 일본 특허 출원(일본 특허 출원 제2017-066987호)에 근거하고 있으며, 그 전체 내용은 본원에 참고로 포함된다. 또한, 본원에 인용되는 모든 참조 문헌은 전체로서 포함된다.In addition, this application is based on the Japanese patent application (Japanese Patent Application No. 2017-066987) for which it applied on March 30, 2017, The whole content is taken in here by reference. Also, all references cited herein are incorporated in their entirety.
Claims (8)
(식 (1) 중, X1 및 Y1은 각각 생체기능성 분자에 존재하는 관능기와 반응하여 공유결합을 형성하는 관능기를 적어도 포함하는 원자단이며, 원자단 X1이 포함하는 상기 관능기와 원자단 Y1이 포함하는 상기 관능기는 서로 상이하고;
R1은 탄소수 1 내지 7의 탄화수소기 또는 수소 원자이고;
n은 3 내지 72의 정수이고;
A1은 -NHC(O)-(CH2)m1- 또는 -NHC(O)-(CH2)m1-L2-(CH2)m2-를 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수를 나타내고;
B1은 -(CH2)m3- 또는 -(CH2)m3-L4-(CH2)m4-를 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수를 나타낸다.)The heterobifunctional monodisperse polyethylene glycol represented by Formula (1).
(In Formula (1), X 1 and Y 1 are each an atomic group including at least a functional group that reacts with a functional group present in the biofunctional molecule to form a covalent bond, and the functional group and atomic group Y 1 included in the atomic group X 1 are The functional groups comprising are different from each other;
R 1 is a hydrocarbon group having 1 to 7 carbon atoms or a hydrogen atom;
n is an integer from 3 to 72;
A 1 represents -NHC(O)-(CH 2 ) m1- or -NHC(O)-(CH 2 ) m1 -L 2 -(CH 2 ) m2 -, L 2 is an ether bond, an amide bond or a urethane represents a bond, and m1 and m2 each independently represent an integer of 1 to 5;
B 1 represents -(CH 2 ) m3 - or -(CH 2 ) m3 -L 4 -(CH 2 ) m4 -, L 4 represents an ether bond, an amide bond or a urethane bond, and m3 and m4 are each independently represents an integer from 1 to 5.)
(식 (1) 중, X1 및 Y1은 각각 생체기능성 분자에 존재하는 관능기와 반응하여 공유결합을 형성하는 관능기를 적어도 포함하는 원자단이며, 원자단 X1이 포함하는 상기 관능기와 원자단 Y1이 포함하는 상기 관능기는 서로 상이하고;
R1은 탄소수 1 내지 7의 탄화수소기 또는 수소 원자이고;
n은 3 내지 72의 정수이고;
A1은 -O-(CH2)m1- 또는 -O-(CH2)m1-L2-(CH2)m2-를 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수를 나타내고;
B1은 -CH2- 또는 -CH2-L4-(CH2)m4-를 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m4는 1 내지 5의 정수를 나타낸다.)The heterobifunctional monodisperse polyethylene glycol represented by Formula (1).
(In Formula (1), X 1 and Y 1 are each an atomic group including at least a functional group that reacts with a functional group present in the biofunctional molecule to form a covalent bond, and the functional group and atomic group Y 1 included in the atomic group X 1 are The functional groups comprising are different from each other;
R 1 is a hydrocarbon group having 1 to 7 carbon atoms or a hydrogen atom;
n is an integer from 3 to 72;
A 1 represents -O-(CH 2 ) m1 - or -O-(CH 2 ) m1 -L 2 -(CH 2 ) m2 -, L 2 represents an ether bond, an amide bond or a urethane bond, m1 and m2 each independently represents an integer of 1 to 5;
B 1 represents -CH 2 - or -CH 2 -L 4 -(CH 2 ) m4 -, L 4 represents an ether bond, an amide bond or a urethane bond, and m4 represents an integer of 1 to 5.)
(식 (1) 중, X1 및 Y1은 각각 생체기능성 분자에 존재하는 관능기와 반응하여 공유결합을 형성하는 관능기를 적어도 포함하는 원자단이며, 원자단 X1이 포함하는 상기 관능기와 원자단 Y1이 포함하는 상기 관능기는 서로 상이하고;
R1은 탄소수 1 내지 7의 탄화수소기 또는 수소 원자이고;
n은 3 내지 72의 정수이고;
A1은 -C(O)NH-(CH2)m1- 또는 -C(O)NH-(CH2)m1-L2-(CH2)m2-를 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수를 나타내고;
B1은 -CH2- 또는 -CH2-L4-(CH2)m4-를 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m4는 1 내지 5의 정수를 나타낸다.)The heterobifunctional monodisperse polyethylene glycol represented by Formula (1).
(In Formula (1), X 1 and Y 1 are each an atomic group including at least a functional group that reacts with a functional group present in the biofunctional molecule to form a covalent bond, and the functional group and atomic group Y 1 included in the atomic group X 1 are The functional groups comprising are different from each other;
R 1 is a hydrocarbon group having 1 to 7 carbon atoms or a hydrogen atom;
n is an integer from 3 to 72;
A 1 represents -C(O)NH-(CH 2 ) m1- or -C(O)NH-(CH 2 ) m1 -L 2 -(CH 2 ) m2 -, L 2 is an ether bond, an amide bond or a urethane bond, and m1 and m2 each independently represent an integer of 1 to 5;
B 1 represents -CH 2 - or -CH 2 -L 4 -(CH 2 ) m4 -, L 4 represents an ether bond, an amide bond or a urethane bond, and m4 represents an integer of 1 to 5.)
(식 (1) 중, X1 및 Y1은 각각 생체기능성 분자에 존재하는 관능기와 반응하여 공유결합을 형성하는 관능기를 적어도 포함하는 원자단이며, 원자단 X1이 포함하는 상기 관능기와 원자단 Y1이 포함하는 상기 관능기는 서로 상이하고;
R1은 탄소수 1 내지 7의 탄화수소기 또는 수소 원자이고;
n은 3 내지 72의 정수이고;
A1은 -C(O)NH-(CH2)m1- 또는 -C(O)NH-(CH2)m1-L2-(CH2)m2-를 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수를 나타내고;
B1은 -C(O)NH-(CH2)m3- 또는 -C(O)NH-(CH2)m3-L4-(CH2)m4-를 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수를 나타낸다.)The heterobifunctional monodisperse polyethylene glycol represented by Formula (1).
(In Formula (1), X 1 and Y 1 are each an atomic group including at least a functional group that reacts with a functional group present in the biofunctional molecule to form a covalent bond, and the functional group and atomic group Y 1 included in the atomic group X 1 are The functional groups comprising are different from each other;
R 1 is a hydrocarbon group having 1 to 7 carbon atoms or a hydrogen atom;
n is an integer from 3 to 72;
A 1 represents -C(O)NH-(CH 2 ) m1- or -C(O)NH-(CH 2 ) m1 -L 2 -(CH 2 ) m2 -, L 2 is an ether bond, an amide bond or a urethane bond, and m1 and m2 each independently represent an integer of 1 to 5;
B 1 represents -C(O)NH-(CH 2 ) m3 - or -C(O)NH-(CH 2 ) m3 -L 4 -(CH 2 ) m4 -, L 4 is an ether bond, an amide bond or a urethane bond, and m3 and m4 each independently represent an integer of 1 to 5.)
(식 (1) 중, X1 및 Y1은 각각 생체기능성 분자에 존재하는 관능기와 반응하여 공유결합을 형성하는 관능기를 적어도 포함하는 원자단이며, 원자단 X1이 포함하는 상기 관능기와 원자단 Y1이 포함하는 상기 관능기는 서로 상이하고, X1 및 Y1이, 각각 독립적으로 식 (a), 식 (b1), 식 (b2), 식 (c), 식 (d), 식 (e), 식 (f), 식 (g), 식 (h), 식 (i), 식 (j), 식 (k), 식 (l), 식 (m), 식 (n) 및 식 (o)로 구성되는 군으로부터 선택되고;
R1은 탄소수 1 내지 7의 탄화수소기 또는 수소 원자이고;
n은 3 내지 72의 정수이고;
A1은 -L1-(CH2)m1-, -L1-(CH2)m1-L2-(CH2)m2- 또는 단결합을 나타내고, L1은 에테르 결합, 아미드 결합, 우레탄 결합, 2급 아미노기 또는 단결합을 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수를 나타내고;
B1은 -L3-(CH2)m3-, -L3-(CH2)m3-L4-(CH2)m4- 또는 단결합을 나타내고, L3은 아미드 결합 또는 단결합을 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수를 나타낸다.)
(식 (d) 중, R2는 수소 원자 또는 탄소수 1 내지 5의 탄화수소기이고;
식 (e) 중, R3은 염소 원자, 브롬 원자 및 요오드 원자로부터 선택되는 할로겐 원자이고;
식 (l) 중, R4는 수소 원자 또는 탄소수 1 내지 5의 탄화수소기이다.)The heterobifunctional monodisperse polyethylene glycol represented by Formula (1).
(In Formula (1), X 1 and Y 1 are each an atomic group including at least a functional group that reacts with a functional group present in the biofunctional molecule to form a covalent bond, and the functional group and atomic group Y 1 included in the atomic group X 1 are The functional groups comprising are different from each other, and X 1 and Y 1 are each independently formula (a), formula (b1), formula (b2), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), selected from the group consisting of formula (j), formula (k), formula (l), formula (m), formula (n) and formula (o);
R 1 is a hydrocarbon group having 1 to 7 carbon atoms or a hydrogen atom;
n is an integer from 3 to 72;
A 1 represents -L 1 -(CH 2 ) m1 -, -L 1 -(CH 2 ) m1 -L 2 -(CH 2 ) m2 - or a single bond, and L 1 represents an ether bond, an amide bond, or a urethane bond. , a secondary amino group or a single bond, L 2 represents an ether bond, an amide bond, or a urethane bond, m1 and m2 each independently represent an integer of 1 to 5;
B 1 represents -L 3 -(CH 2 ) m3 -, -L 3 -(CH 2 ) m3 -L 4 -(CH 2 ) m4 - or a single bond, L 3 represents an amide bond or a single bond, L 4 represents an ether bond, an amide bond, or a urethane bond, and m3 and m4 each independently represent an integer of 1 to 5.)
(in formula (d), R 2 is a hydrogen atom or a hydrocarbon group having 1 to 5 carbon atoms;
In formula (e), R 3 is a halogen atom selected from a chlorine atom, a bromine atom and an iodine atom;
In formula (1), R 4 is a hydrogen atom or a hydrocarbon group having 1 to 5 carbon atoms.)
(식 (2) 중, X2 및 Y2 중 하나는 항체이고, 다른 하나는 약물이고;
R1은 탄소수 1 내지 7의 탄화수소기 또는 수소 원자이고;
n는 3 내지 72의 정수이고;
A2은 -L1-(CH2)m1-L5-, -L1-(CH2)m1-L2-(CH2)m2-L5- 또는 단결합을 나타내고, L1은 에테르 결합, 아미드 결합, 우레탄 결합, 2급 아미노기 또는 단결합을 나타내고, L2는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m1 및 m2는 각각 독립적으로 1 내지 5의 정수를 나타내고, L5는 아미드 결합, 우레탄 결합, 티오에테르 결합, 디술피드 결합, 카보네이트 결합, 에스테르 결합, 에테르 결합, 1H-1,2,3-트리아졸-1,4-디일 구조, 2급 아미노기, 히드라지드기, 옥시아미드기 또는 이들 중 어느 것을 포함하는 탄화수소기이고;
B2은 -L3-(CH2)m3-L6-, -L3-(CH2)m3-L4-(CH2)m4-L6- 또는 단결합을 나타내고, L3은 아미드 결합 또는 단결합을 나타내고, L4는 에테르 결합, 아미드 결합 또는 우레탄 결합을 나타내고, m3 및 m4는 각각 독립적으로 1 내지 5의 정수를 나타내고, L6는 아미드 결합, 우레탄 결합, 티오에테르 결합, 디술피드 결합, 카보네이트 결합, 에스테르 결합, 에테르 결합, 1H-1,2,3-트리아졸-1,4-디일 구조, 2급 아미노기, 히드라지드기, 옥시아미드기 또는 이들 중 어느 것을 포함하는 탄화수소기이다.)Represented by Formula (2), the antibody-drug complex comprising heterobifunctional monodisperse polyethylene glycol.
(in formula (2), one of X 2 and Y 2 is an antibody and the other is a drug;
R 1 is a hydrocarbon group having 1 to 7 carbon atoms or a hydrogen atom;
n is an integer from 3 to 72;
A 2 represents -L 1 -(CH 2 ) m1 -L 5 -, -L 1 -(CH 2 ) m1 -L 2 -(CH 2 ) m2 -L 5 - or a single bond, L 1 is an ether bond , represents an amide bond, a urethane bond, a secondary amino group or a single bond, L 2 represents an ether bond, an amide bond or a urethane bond, m1 and m2 each independently represent an integer of 1 to 5, L 5 is an amide bond , urethane bond, thioether bond, disulfide bond, carbonate bond, ester bond, ether bond, 1H-1,2,3-triazole-1,4-diyl structure, secondary amino group, hydrazide group, oxyamide group or a hydrocarbon group containing any of these;
B 2 represents -L 3 -(CH 2 ) m3 -L 6 -, -L 3 -(CH 2 ) m3 -L 4 -(CH 2 ) m4 -L 6 - or a single bond, and L 3 is an amide bond or a single bond, L 4 represents an ether bond, an amide bond, or a urethane bond, m3 and m4 each independently represent an integer of 1 to 5, L 6 is an amide bond, a urethane bond, a thioether bond, a disulfide a bond, a carbonate bond, an ester bond, an ether bond, a 1H-1,2,3-triazole-1,4-diyl structure, a secondary amino group, a hydrazide group, an oxyamide group, or a hydrocarbon group containing any of these .)
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